Hdm2-inhibitor complexes and uses thereof

ABSTRACT

The present invention includes crystallized HDM2 peptides as well as descriptions of the X-ray diffraction patterns of the crystals. The diffraction patterns allow the three dimensional structure of HDM2 to be determined at atomic resolution so that ligand binding sites on HDM2 can be identified and the interactions of ligands with HDM2 amino acid residues can be modeled. Models prepared using such maps permit the design of ligands which can function as active agents which include, but are not limited to, those that function as inhibitors of MDM2 and HDM2 oncoproteins.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to Application No. 60/418,350 filed on Oct. 16, 2002.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH DEVELOPMENT

Not applicable.

FIELD OF THE INVENTION

The present invention generally pertains to the fields of molecular biology, protein crystallization, X-ray diffraction analysis, three-dimensional structural determination, molecular modeling and structure based rational drug design. The present invention provides crystallized HDM2 peptides as well as descriptions of the X-ray diffraction patterns. The X-ray diffraction patterns of the crystals in question are of sufficient resolution so that the three-dimensional structure of HDM2 can be determined at atomic resolution, ligand binding sites on HDM2 can be identified, and the interactions of ligands with HDM2 amino acid residues can be modeled.

The high resolution maps provided by the present invention and the models prepared using such maps also permit the design of ligands which can function as active agents. Thus, the present invention has applications to the design of active agents which include, but are not limited to, those that find use as inhibitors of MDM2 and HDM2 oncoproteins.

BACKGROUND OF THE INVENTION

HDM2: Structure and Function

HDM2 (human double minute 2 protein) is the expression product of hdm2, an oncogene that is overexpressed in a subset of human tumors including soft tissue sarcomas, glioblastomas and mammary carcinomas (Oliner, J. D. et al., Nature, 358(6381):80-83 (1992); Reifenberger, G. et al., Cancer Res., 53:2736-2739 (1993); Bueso-Ramos, C. E. et al., Breast Canc. Res. Treat., 37(2):179-188 (1996)).

Functional characterization of this oncogene revealed an interaction between HDM2 and p53, a tumor suppressor central to cell growth arrest and apoptosis (Momand, G. P. et al., Cell, 69:1237 (1992)). HDM2 is a transcriptional target of p53, and as such, HDM2 and p53 form a precisely regulated loop (Wu, X. et al., Genes and Dev., 7:1126-1132 (1992)). HDM2 is further regulated by ubiquitination and by complex formation with Arf, which sequesters HDM2 to the nucleolus (Tao, W. and Levine, A. J., Proc. Natl. Acad. Sci. USA, 96(12):6937-6941 (1999); Weber, J. D. et al., Nat. Cell Biol., 1(1):20-26 (1999)).

There are several lines of evidence that suggest that HDM2 can also function independently of p53. Splice variants of HDM2 not containing the p53-binding domain have been found in human tumors and have been shown to possess transforming ability (Sigalas, I. et al. Nat. Med. 2(8):912-917 (1996)). In vivo studies have also demonstrated that the spectrum of tumors that develop in transgenic mice overexpressing HDM2 is different from the spectrum found in p53-null mice and that HDM2 can drive sarcomagenesis in p53-null animals (Jones, S, N. et al., Proc. Natl. Acad. Sci. USA, 95(26):15608-15612 (1998)). Lastly, other binding partners of HDM2 could assist HDM2 function along an oncogenic pathway, for example, HDM2 inhibition of MTBP-induced p53-independent G1 arrest (Boyd, M. T. et al., J. Biol. Chem. 275(41):31883-31890 (2000)).

Reports of enhanced tumor cell death following hdm2 inhibition by antisense nucleotides (Chen, L. et al., Proc. Natl. Acad. Sci. USA, 95(1):195-200 (1998); Chen, L. et al., Mol. Med., 5(1):21-34 (1999); Tortora, G. et al., Int. J. Cancer, 88(5):804-809 (2000)) and HDM2-binding mini-proteins (Bottger, A. et al., Curr. Biol., 7(11):860-869 (1997)) substantiate a prediction that inhibition of HDM2 will activate p53 and in turn trigger apoptosis. Following on this idea, a small molecule inhibitor generated against the p53 binding groove of HDM2 would be expected to prevent the interaction of the two proteins and induce p53 activity. It has been further suggested that inhibiting the interaction between p53 and HDM2 will act additively or synergistically with standard chemotherapeutic agents in the treatment of neoplasm, and this too is supported by work utilizing antisense hdm2 constructs (Wang, H. et al., Clin. Canc. Res. 7(11):3613-3624 (2001)).

MDM2: Structure and Function

mdm2, the murine homolog of HDM2 was originally found on mouse double minute chromosomes and was initially identified as one of three genes amplified in a tumorigenic cell line (Cahilly-Snyder., L. et al., Somatic Cell Mol. Genet. 13:235-244 (1987)). Its protein product was subsequently found to form a complex with p53, which was first observed in a rat fibroblast cell line (Clone 6) previously transfected with a temperature sensitive mouse p53 gene (Michalovitz, D. et al., Cell 62:671-680 (1990)). The rat cell line grew well at 37° C. but exhibited a G1 arrest when shifted down to 32° C., which was entirely consistent with an observed temperature dependent switch in p53 conformation and activity. However, the p53-MDM2 complex was only observed in abundance at 32° C., at which temperature p53 was predominantly in a functional or “wild-type” form (Barak, Y. et al., EMBO J. 11:2115-2121 (1992) and Momand, J. et al., Cell 69:1237-1245 (1992)). By shifting the rat cell line down to 32° C. and blocking de novo protein synthesis it was shown that only “wild-type” p53 induced expression of the mdm2 gene, thereby accounting for the differential abundance of the complex in terms of p53 transcriptional activity (Barak, Y. et al., EMBO J. 12:461-468 (1993)). The explanation was further developed by the identification of a DNA binding site for wild-type p53 within the first intron of the mdm2 gene (Wu, X. et al., Genes Dev. 7:1126-1132 (1993)). Reporter constructs employing this p53 DNA binding site revealed that they were inactivated when wild-type p53 was co-expressed with MDM2.

This inhibition of the transcriptional activity of p53 may be caused by MDM2 blocking the activation domain of p53 and/or the DNA binding site. Consequently, it was proposed that mdm2 expression is autoregulated, via the inhibitory effect of MDM2 protein on the transcriptional activity of wild-type p53. This p53-mdm2 autoregulatory feedback loop provided a novel insight as to how cell growth might be regulated by p53. Up to a third of human sarcomas are considered to overcome p53-regulated growth control by amplification of the mdm2 gene (Oliner, J. D. et al., Nature 358:80-83 (1992)). Hence, the interaction between p53 and MDM2 represents a key potential therapeutic target.

p53: Interaction with HDM2 and MDM2

p53 is a transcription factor for a number of proteins that cause cell cycle arrest or cell death by apoptosis, such as p21, 14-3-3σ, and bax. The level and transcriptional activity of p53 are increased by damage to cellular DNA. The MDM2 protein inhibits p53 function by binding to an amphipathic N-terminal helix of p53, abrogating the interaction of p53 with other proteins and its transactivation activity. The interaction with MDM2 also targets p53 for ubiquitin dependent protein degradation. MDM2 exhibits p53 independent effects on cell cycling as well, possibly by direct interaction with some of the downstream effectors such as pRB and EF2 (Reviewed in Zhang, R. and Wang, H., Cur. Pharm. Des. 6:393-416 (2000)).

Mutations of the p53 protein occur in 50% of all human cancers (reviewed in Agarwal, M. L. et al. J. Biol. Chem. 273:1-4 (1998); Levine, A. J., Cell 88:323-331 (1997); and, references cited in Oren, M., J. Biol. Chem. 274:36031-36034 (1999)). Under normal circumstances, p53 is latent and a very labile protein, which turns over with a very short half-life of a few minutes (Rogel, A. et al., Mol. Cell. Biol. 5:2851-2855 (1985)). DNA damage or stress induces a remarkable increase in the stability of p53 (Kastan, M. B. et al., Cancer Res. 51:6304-6311 (1991)). Furthermore, these signals also activate the function of p53 as a transcriptional activator of the apoptotic machinery, a function normally suppressed by autoregulatory inhibition of its transactivation domain. The amount of p53 present in the cell is tightly regulated by a negative feedback loop between p53 and the oncogene hdm2.

p53 is located in the cell nucleus and induces the expression of hdm2 through its transactivation domain. Expressed hdm2 subsequently binds to residues 19-26 of the p53 transactivation domain, inactivates it (Chen, J. et al., Mol. Cell. Biol. 16:2445-2452 (1996); Haupt, Y. et al., EMBO J. 15:1596-1606 (1996); Momand, J. et al., Cell 69:1237-1245 (1992)) and blocks recruitment of transcription factors necessary for gene expression (Lu, H. et al., PNAS 92:5154-5158 (1995); Thut, C. J. et al., Science 267:00-104 (1995)). Furthermore, the p53-hdm2-complex is shuttled to the cytoplasm where degradation occurs. This tight control through negative feedback is critical for the survival of the organism. Inactivation of hdm2 in hdm2-knockout mice leads to early embryonal lethality, but is completely prevented by simultaneous inactivation of p53 (Jones, S, N. et al., Nature 378:206-208 (1995); Montes de Oca Luna, R. et al., Nature 378:203-206 (1995)). On the other hand, excessive expression of hdm2 can lead to constitutive inhibition of p53 and promote cancer. Excess HDM2 also promotes cancer independently of p53 (Lundgren, K. et al., Genes and Dev. 11:714-725 (1997); Sun, P. et al., Science 282:2270-2272 (1998)).

As discussed above, inhibition of the interaction between HDM2 and p53 is an attractive target for cancer therapy (Lane, D. P., TIBS 22: 372-374 (1997)). It has been shown that inhibition of the complex formation between p53 and HDM2 raises the levels of p53 in the cell (Bottger, A. et al., Current Biol. 7:860-869 (1997)). Also, blocking HDM2 from binding p53 would be therapeutically useful in restoring cell cycle control to cells that overexpress HDM2 as a front line cancer treatment. More generally, inhibition of HDM2 may increase the effectiveness of chemotherapy and radiation in p53 normal cancers by enhancing apoptosis and growth arrest signaling pathways. This approach may render tumor cells containing functional p53 more susceptible to chemotherapeutic agents.

One method of identifying inhibitors of the p53/HDM2 protein complex is to determine the amino acid specificities of HDM2 binding pockets by crystallography in order to establish a model for the interaction. Using this method, Kussie et al. identified p53 based peptide antagonists (Kussie, P. H. et al., Science 274:948-953 (1996)). A crystal structure of a truncated form of HDM2 (residues 17-125) and a 15′mer peptide derived from the N-terminal transactivation domain of p53 was published by Kussie et al. (Kussie et al., (1996)). Kussie et al. also published a crystal structure of MDM2 (Kussie et al., (1996)) derived from Xenopus laevis (residues 13 to 118), having a 71% sequence identity towards HDM2. Based on molecular modeling, Garcìa-Echeverrìa et al. published a model of an 8′mer peptidomimetic, derived from the 15′mer wild-type p53 peptide, bound to the N-terminal domain of hdm2 (Garcìa-Echeverrìa, C. et al., J. Med. Chem. 43:3205-3208 (2000)). No crystal structure of HDM2 with inhibitory compounds, such as small molecule inhibitors, for example, or other peptides is believed to have been disclosed.

Therefore, a need continues to exist for the development of modeling systems to design and select potent, small molecules that inhibit the interactions between HDM2 (and homologs thereof) and natural binding ligands such as p53.

SUMMARY OF THE INVENTION

The present invention includes methods of producing and using three-dimensional structure information derived from human MDM2 protein (HDM2) and inhibitory compounds which form a complex with HDM2 and prevent HDM2 from interacting with the p53 protein. The present invention also includes specific crystallization conditions to obtain crystals of the inhibitor-HDM2 complex. The crystals are subsequently used to obtain a 3-dimensional structure of the complex using X-ray crystallography (or NMR) and the obtained data is used for rational drug discovery design with the aim to improve the complex formation between HDM2 and the inhibitor, and, also to improve the inhibition of the binding of HDM2 to p53.

The present invention includes a crystal comprising HDM2, or a fragment, or target structural motif or derivative thereof, and a ligand, wherein the ligand is a small molecule inhibitor. In another embodiment, the crystal has a spacegroup selected from the group consisting of a trigonal spacegroup of P3₂21 and a tetragonal spacegroup P4₃2₁2. The present invention also includes a crystal comprising HDM2 which comprises a peptide having at least 95% sequence identity to SEQ ID NO. 2.

In another aspect of the invention, the invention includes a computer system comprising: (a) a database containing information on the three dimensional structure of a crystal comprising HDM2, or a fragment or a target structural motif or derivative thereof, and a ligand, wherein the ligand is a small molecule inhibitor, stored on a computer readable storage medium; and, (b) a user interface to view the information.

The present invention also includes a method of evaluating the potential of an agent to associate with HDM2 comprising: (a) exposing HDM2 to the agent; and (b) detecting the association of said agent to HDM2 amino acid residues Ser¹⁷, Ile¹⁹, Leu¹² and Arg⁹⁷ thereby evaluating the potential.

The invention further includes a method of evaluating the potential of an agent to associate with the peptide having aa¹⁶-SEQ ID NO: 2, comprising: (a) exposing aa¹⁶-SEQ ID NO: 2 to the agent; and (b) detecting the level of association of the agent to aa¹⁶-SEQ ID NO: 2, thereby evaluating the potential.

Further included in the present invention is a method of identifying a potential agonist or antagonist against HDM2 comprising: (a) employing the three dimensional structure of HDM2 cocrystallized with a small molecule inhibitor to design or select said potential agonist or antagonist.

The instant invention comprises a method of locating the attachment site of an inhibitor to HDM2, comprising: (a) obtaining X-ray diffraction data for a crystal of HDM2; (b) obtaining X-ray diffraction data for a complex of HDM2 and an inhibitor; (c) subtracting the X-ray diffraction data obtained in step (a) from the X-ray diffraction data obtained in step (b) to obtain the difference in the X-ray diffraction data; (d) obtaining phases that correspond to X-ray diffraction data obtained in step (a); (e) utilizing the phases obtained in step (d) and the difference in the X-ray diffraction data obtained in step (c) to compute a difference Fourier image of the inhibitor; and, (f) locating the attachment site of the inhibitor to HDM2 based on the computations obtained in step (e).

The present invention further comprises a method of obtaining a modified inhibitor comprising: (a) obtaining a crystal comprising HDM2 and an inhibitor; (b) obtaining the atomic coordinates of the crystal; (c) using the atomic coordinates and one or more molecular modeling techniques to determine how to modify the interaction of the inhibitor with HDM2; and, (d) modifying the inhibitor based on the determinations obtained in step (c) to produce a modified inhibitor.

In another aspect of the invention, the invention includes an isolated protein fragment comprising a binding pocket or active site defined by structure coordinates of HDM2 amino acid residues Ser¹⁷, Ile¹⁹, Leu⁸² and Arg⁹⁷.

In another aspect of the invention, the invention includes an isolated nucleic acid molecule encoding the fragment which comprises a binding pocket or active site defined by structure coordinates of HDM2 amino acid residues Ser¹⁷, Ile¹⁹, Leu⁸² and Arg⁹⁷. In another aspect of the invention, the invention includes a method of screening for an agent that associates with HDM2, comprising: (a) exposing a protein molecule fragment to the agent; and (b) detecting the level of association of the agent to the fragment. In another aspect of the invention, the invention includes a kit comprising a protein molecule fragment.

The invention additionally comprises a method for the production of a crystal complex comprising an HDM2 polypeptide-ligand comprising: (a) contacting the HDM2 polypeptide with said ligand in a suitable solution comprising PEG and NaSCN; and, b) crystallizing said resulting complex of HDM2 polypeptide-ligand from said solution.

The invention further includes a method for the production of a crystal comprising HDM2 and a ligand wherein the ligand is a small molecule inhibitor comprising crystallizing a peptide comprising a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO:4 with a potential inhibitor.

The instant invention includes a method for identifying a potential inhibitor of HDM2 comprising: a) using a three dimensional structure of HDM2 as defined by atomic coordinates according to table 1 or table 2; b) replacing one or more HDM2 amino acids selected from Ser¹⁷, Ile¹⁹, Leu⁸² and Arg¹⁹ in said three-dimensional structure with a different amino acid to produce a modified HDM2; c) using said three-dimensional structure to design or select said potential inhibitor; d) synthesizing said potential inhibitor; and, e) contacting said potential inhibitor with said modified HDM2 in the presence of a substrate to test the ability of said potential inhibitor to inhibit HDM2 or said modified HDM2. Also included in the invention is an inhibitor identified by the method.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 Ribbon representation of HDM2 bound to compound 338437.

FIG. 2 Fit of compound 338437 into the active site of HDM2 represented as a molecular surface.

FIG. 3 Ribbon representation of a superposition between hdm2 in the trigonal crystal form and in the tetragonal form. The RMS deviation between C-alpha atom positions is 0.25 Angstroms.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As is generally the case in biotechnology and chemistry, the description of the present invention has required the use of a number of terms of art. Although it is not practical to do so exhaustively, definitions for some of these terms are provided here for ease of reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Definitions for other terms also appear elsewhere herein. However, the definitions provided here and elsewhere herein should always be considered in determining the intended scope and meaning of the defined terms. Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred methods and materials are described.

As used herein, the term “atomic coordinates” or “structure coordinates” refers to mathematical coordinates that describe the positions of atoms in crystals of HDM2 in Protein Data Bank (PDB) format, including X, Y, Z and B, for each atom. The diffraction data obtained from the crystals are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps may be used to establish the positions (i.e. coordinates X, Y and Z) of the individual atoms within the crystal. Those of skill in the art understand that a set of structure coordinates determined by X-ray crystallography is not without standard error. For the purpose of this invention, any set of structure coordinates for HDM2 from any source having a root mean square deviation of non-hydrogen atoms of less than about 1.5 Å when superimposed on the non-hydrogen atom positions of the corresponding atomic coordinates of Table 1 or Table 2 are considered substantially identical or homologous. In a more preferred embodiment, any set of structure coordinates for HDM2 from any source having a root mean square deviation of non-hydrogen atoms of less than about 0.75 Å when superimposed on the non-hydrogen atom positions of the corresponding atomic coordinates of Table 1 or Table 2 are considered substantially identical or homologous.

The term “atom type” refers to the chemical element whose coordinates are measured. The first letter in a column in Table 1 identifies the element.

The terms “X,” “Y” and “Z” refer to the crystallographically-defined atomic position of the element measured with respect to the chosen crystallographic origin. The term “B” refers to a thermal factor that measures the mean variation of an atom's position with respect to its average position.

As used herein, the term “crystal” refers to any three-dimensional ordered array of molecules that diffracts X-rays.

As used herein, the term “carrier” in a composition refers to a diluent, adjuvant, excipient, or vehicle with which the product is mixed.

As used herein, the term “composition” refers to the combining of distinct elements or ingredients to form a whole. A composition comprises more than one element or ingredient. For the purposes of this invention, a composition will often, but not always, comprise a carrier.

As used herein, “mdm2” is used to mean the murine double minute 2 gene, and homologous genes found in other animals.

As used herein, “MDM2” is used to mean a protein obtained as a result of expression of the mdm2 oncogene. Within the meaning of this term, it will be understood that MDM2 encompasses all proteins encoded by mdm2, mutants thereof, conservative amino acid substitutions, alternative splice proteins thereof, and phosphorylated proteins thereof. Additionally, as used herein, it will be understood that the term “MDM2” includes MDM2 homologues of other animals.

As used herein, “hdm2” is used to mean the human gene, which is homologous to the mouse mdm2 gene.

As used herein, “HDM2” is used to mean a protein obtained as a result of expression of the hdm2 oncogene. Within the meaning of this term, it will be understood that HDM2 encompasses all proteins encoded by hdm2, mutants thereof, conservative amino acid substitutions, alternative splice proteins thereof, and phosphorylated proteins thereof. As an example, HDM2 includes the protein comprising SEQ ID NO: 2 and variants thereof comprising at least about 70% amino acid sequence identity to SEQ ID NO: 2, or preferably 80%, 85%, 90% and 95% sequence identity to SEQ ID NO: 2, or more preferably, at least about 95% or more sequence identity to SEQ ID NO: 2.

As used herein, the term “SAR,” an abbreviation for Structure-Activity Relationships, collectively refers to the structure-activity/structure property relationships pertaining to the relationship(s) between a compound's activity/properties and its chemical structure.

As used herein, the term “molecular structure” refers to the three dimensional arrangement of molecules of a particular compound or complex of molecules (e.g., the three dimensional structure of HDM2 and ligands that interact with HDM2).

As used herein, the term “molecular modeling” refers to the use of computational methods, preferably computer assisted methods, to draw realistic models of what molecules look like and to make predictions about structure activity relationships of ligands. The methods used in molecular modeling range from molecular graphics to computational chemistry.

As used herein, the term “molecular model” refers to the three dimensional arrangement of the atoms of a molecule connected by covalent bonds or the three dimensional arrangement of the atoms of a complex comprising more than one molecule, e.g. a protein-ligand complex.

As used herein, the term “molecular graphics” refers to 3D representations of the molecules, for instance, a 3D representation produced using computer assisted computational methods.

As used herein, the term “computational chemistry” refers to calculations of the physical and chemical properties of the molecules.

As used herein, the term “molecular replacement” refers to a method that involves generating a preliminary model of a crystal of HDM2 whose coordinates are unknown, by orienting and positioning the said atomic coordinates described in the present invention so as best to account for the observed diffraction pattern of the unknown crystal. Phases can then be calculated from this model and combined with the observed amplitudes to give an approximate Fourier synthesis of the structure whose coordinates are unknown. (Rossmann, M. G., ed., “The Molecular Replacement Method”, Gordon & Breach, New York, 1972).

As used herein, the term “homolog” refers to the HDM2 protein molecule or the nucleic acid molecule which encodes the protein, or a functional domain from said protein from a first source having at least about 30%, 40% or 50% sequence identity, or at least about 60%, 70% or 75% sequence identity, or at least about 80% sequence identity, or more preferably at least about 85% sequence identity, or even more preferably at least about 90% sequence identity, and most preferably at least about 95%, 97% or 99% amino acid or nucleotide sequence identity, with the protein, encoding nucleic acid molecule or any functional domain thereof, from a second source. The second source may be a version of the molecule from the first source that has been genetically altered by any available means to change the primary amino acid or nucleotide sequence or may be from the same or a different species than that of the first source.

As used herein, the term “active site” refers to regions on HDM2 or a structural motif of HDM2 that are directly involved in the function or activity of HDM2.

As used herein, the terms “binding site” or “binding pocket” refer to a region of HDM2 or a molecular complex comprising HDM2 that, as a result of the primary amino acid sequence of HDM2 and/or its three-dimensional shape, favorably associates with another chemical entity or compound including ligands or inhibitors.

For the purpose of this invention, any active site, binding site or binding pocket defined by a set of structure coordinates for HDM2 or for a homolog of HDM2 from any source having a root mean square deviation of non-hydrogen atoms of less than about 1.5 Å when superimposed on the non-hydrogen atom positions of the corresponding atomic coordinates of Table 1 or Table 2 are considered substantially identical or homologous. In a more preferred embodiment, any set of structure coordinates for HDM2 or a homolog of HDM2 from any source having a root mean square deviation of non-hydrogen atoms of less than about 0.75 Å when superimposed on the non-hydrogen atom positions of the corresponding atomic coordinates of Table 1 or Table 2 are considered substantially identical or homologous.

The term “root mean square deviation” means the square root of the arithmetic mean of the squares of the deviations from the mean.

As used herein, the term “amino acids” refers to the L-isomers of the naturally occurring amino acids. The naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, γ-carboxylglutamic acid, arginine, ornithine, and lysine. Unless specifically indicated, all amino acids are referred to in this application are in the L-form.

As used herein, the term “nonnatural amino acids” refers to amino acids that are not naturally found in proteins. For example, selenomethionine.

As used herein, the term “positively charged amino acid” includes any amino acids having a positively charged side chain under normal physiological conditions. Examples of positively charged naturally occurring amino acids are arginine, lysine, and histidine.

As used herein, the term “negatively charged amino acid” includes any amino acids having a negatively charged side chains under normal physiological conditions. Examples of negatively charged naturally occurring amino acids are aspartic acid and glutamic acid.

As used herein, the term “hydrophobic amino acid” includes any amino acids having an uncharged, nonpolar side chain that is relatively insoluble in water. Examples of naturally occurring hydrophobic amino acids are alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine.

As used herein, the term “hydrophilic amino acid” refers to any amino acids having an uncharged, polar side chain that is relatively soluble in water. Examples of naturally occurring hydrophilic amino acids are serine, threonine, tyrosine, asparagine, glutamine and cysteine.

As used herein, the term “hydrogen bond” refers to two hydrophilic atoms (either O or N), which share a hydrogen that is covalently bonded to only one atom, while interacting with the other.

As used herein, the term “hydrophobic interaction” refers to interactions made by two hydrophobic residues or atoms (such as C).

As used herein, the term “conjugated system” refers to more than two double bonds are adjacent to each other, in which electrons are completely delocalized with the entire system. This also includes and aromatic residues.

As used herein, the term “aromatic residue” refers to amino acids with side chains having a delocalized conjugated system. Examples of aromatic residues are phenylalanine, tryptophan, and tyrosine.

As used herein, the phrase “inhibiting the binding” refers to preventing or reducing the direct or indirect association of one or more molecules, peptides, proteins, enzymes, or receptors, or preventing or reducing the normal activity of one or more molecules, peptides, proteins, enzymes or receptors, e.g. preventing or reducing the direct or indirect association of HDM2 and p53.

As used herein, the term “competitive inhibitor” refers to inhibitors that bind to HDM2 at the same sites as its binding partner(s) (e.g., p53), thus directly competing with them. Competitive inhibition may, in some instances, be reversed completely by increasing the substrate concentration.

As used herein, the term “uncompetitive inhibitor” refers to one that inhibits the functional activity of HDM2 by binding to a different site than does its substrate(s) e.g. (p53).

As used herein, the term “non-competitive inhibitor” refers to one that can bind to either the free or p53 bound form of HDM2.

Those of skill in the art may identify inhibitors as competitive, uncompetitive, or non-competitive by computer fitting enzyme kinetic data using standard methods. See, for example, Segel, I. H., Enzyme Kinetics, J. Willey & Sons, (1975).

As used herein, the term “R or S-isomer” refers to two possible stereoisomers of a chiral carbon according to the Cahn-Ingold-Prelog system adopted by International Union of Pure and Applied Chemistry (IUPAC). Each group attached to the chiral carbon is first assigned to a preference or priority a, b, c, or d on the basis of the atomic number of the atom that is directly attached to the chiral carbon. The group with the highest atomic number is given the highest preference a, the group with next highest atomic number is given the next highest preference b; and so on. The group with the lowest preference (d) is then directed away from the viewer. If the trace of a path from a to b to c is counter clockwise, the isomer is designated (S); in the opposite direction, clockwise, the isomer is designated (R).

As used herein, the term “ligand” refers to any molecule, or chemical entity which binds with or to HDM2, a subunit of HDM2, a domain of HDM2, a target structural motif of HDM2 or a fragment of HDM2. Thus, ligands include, but are not limited to, small molecule inhibitors, for example.

As used herein, the term “small molecule inhibitor” refers to compounds useful in the present invention having measurable MDM2 or HDM2 inhibiting activity. In addition to small organic molecules, peptides, antibodies, cyclic peptides and peptidomimetics are contemplated as being useful in the disclosed methods. Excluded from the invention are the p53 peptides disclosed in Kussie et al., Garcìa-Echeverrìa et al., and the peptides derived from phage display which inhibit the binding of mdm2 to p53 (Bottger, V. A., et al., Oncogene 13(10): 2141-2147 (1996)). Preferred inhibitors are small molecules, preferably less than 700 Daltons, and more preferably less than 450 Daltons. Examples of classes of compounds having this property include compounds disclosed in U.S. Provisional Application No. 60/275,629; in U.S. Provisional Application No. 60/331,235; in U.S. Provisional Application No. 60/379,617; and, in U.S. application Ser. No. 10/097,249, incorporated herein in their entirety.

As used herein the terms “bind,” “binding,” “bond,” or “bonded” when used in reference to the association of atoms, molecules, or chemical groups, refer to any physical contact or association of two or more atoms, molecules, or chemical groups.

As used herein, the terms “covalent bond” or “valence bond” refer to a chemical bond between two atoms in a molecule created by the sharing of electrons, usually in pairs, by the bonded atoms.

As used herein, “noncovalent bond” refers to an interaction between atoms and/or molecules that does not involve the formation of a covalent bond between them.

As used herein, the term “native protein” refers to a protein comprising an amino acid sequence identical to that of a protein isolated from its natural source or organism.

SPECIFIC EMBODIMENTS Detailed Embodiments

The present invention includes a crystal comprising HDM2, or a fragment, or target structural motif or derivative thereof, and a ligand, wherein the ligand is a small molecule inhibitor. In one embodiment, the fragment or derivative thereof is a peptide selected from the group consisting of SEQ ID NO: 1 (amino acid sequence of full length HDM2), SEQ ID NO: 2 (amino acid residues 17-111 of SEQ ID NO: 1), SEQ ID NO. 3 (amino acid residues 23-114 of SEQ ID NO: 1) and SEQ ID NO. 4 (Gly¹⁶-SEQ ID NO: 2).

In another embodiment, the crystal has a spacegroup selected from the group consisting of a trigonal spacegroup of P3₂21 and a tetragonal spacegroup of P4₃2₁2. In a different embodiment, the crystal effectively diffracts X-rays for determination of atomic coordinates to a resolution of at least about 3.0 Å. In a preferred embodiment, the ligand is in crystalline form. In a highly preferred embodiment, the ligand is selected from the group consisting of (4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid; [8-Chloro-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid, and, derivatives thereof.

The present invention also includes a crystal comprising HDM2 which comprises a peptide having at least 95% sequence identity to SEQ ID NO. 2. In a preferred embodiment, the crystal comprising SEQ ID NO: 2 comprises an atomic structure characterized by the coordinates of Table 1 or Table 2. In another preferred embodiment, the crystal comprises a unit cell selected from the group consisting of: a cell having dimensions of about 98.6 Å, 98.6 Å and 74.7 Å, and about alpha=90°, beta=90° and gamma=120°; and, a cell having dimensions of about 54.3 Å, 54.3 Å, 83.3 Å and about alpha=90°, beta=90° and gamma=90°.

In another aspect of the invention, the invention includes a computer system comprising: (a) a database containing information on the three dimensional structure of a crystal comprising HDM2, or a fragment or a target structural motif or derivative thereof, and a ligand, wherein the ligand is a small molecule inhibitor, stored on a computer readable storage medium; and, (b) a user interface to view the information. In one embodiment, the information comprises diffraction data obtained from a crystal comprising SEQ ID NO:2. In another embodiment, the information comprises an electron density map of a crystal form comprising SEQ ID NO:2. In a different embodiment, the information comprises the structure coordinates of Table 1 or Table 2 or homologous structure coordinates comprising a root mean square deviation of non-hydrogen atoms of less than about 1.5 Å when superimposed on the non-hydrogen atom positions of the corresponding atomic coordinates of Table 1 or Table 2. In a preferred embodiment, the information comprises structure coordinates comprising a root mean square deviation of non-hydrogen atoms of less than about 0.75 Å when superimposed on the non-hydrogen atom positions of the corresponding atomic coordinates of Table 1 or Table 2. In a highly preferred embodiment, the information comprises the structure coordinates for amino acids Ser¹⁷, Ile¹⁹, Leu⁸² and Arg⁹⁷ according to Table 1 or Table 2 or similar structure coordinates for said amino acids comprising a root mean square deviation of non-hydrogen atoms of less than about 1.5 Å when superimposed on the non-hydrogen atom positions of the corresponding atomic coordinates of Table 1 or Table 2. In another embodiment, the information further comprises the structure coordinates for amino acids Val⁵³, Leu⁵⁴, Phe⁵⁵, Leu⁵⁷, Gly⁵⁸, Gln⁵⁹, Ile⁶¹, Met⁶², Tyr⁶⁷ Gln⁷², His⁷³, Ile⁷⁴, Val⁷⁵, Phe⁸⁶, Phe⁹¹, Val⁹³, Lys⁹⁴, Glu⁹⁵, His⁹⁶, Ile⁹⁹, Tyr¹⁰⁰, Ile¹⁰³ according to Table 1 or Table 2 or similar structure coordinates for said amino acids comprising a root mean square deviation of non-hydrogen atoms of less than about 1.5 Å when superimposed on the non-hydrogen atom positions of the corresponding atomic coordinates of Table 1 or Table 2.

The present invention also includes a method of evaluating the potential of an agent to associate with HDM2 comprising: (a) exposing HDM2 to the agent; and (b) detecting the association of said agent to HDM2 amino acid residues Ser¹⁷, Ile¹⁹, Leu⁸² and Arg⁹⁷ thereby evaluating the potential. In one embodiment of the invention, the agent is a virtual compound. In another embodiment of the invention, step (a) comprises comparing the atomic structure of the compound to the three dimensional structure of HDM2. In a different embodiment, the comparing comprises employing a computational means to perform a fitting operation between the compound and at least one binding site of HDM2. In a preferred embodiment, the binding site is defined by structure coordinates for amino acids Ser¹⁷, Ile¹⁹, Leu⁸² and Arg⁹⁷ according to Table 1 or Table 2 similar structure coordinates for said amino acids comprising a root mean square deviation of non-hydrogen atoms of less than about 1.5 Å when superimposed on the non-hydrogen atom positions of the corresponding atomic coordinates of Table 1 or Table 2. In another different embodiment, the binding site is further defined by structure coordinates for amino acids Val⁵³, Leu⁵⁴, Phe⁵⁵, Leu⁵⁷, Gly⁵⁸, Gln⁵⁹, Ile⁶¹, Met⁶², Tyr⁶⁷, Gln⁷², His⁷¹, Ile⁷⁴, Val⁷⁵, Phe⁸⁶, Phe⁹¹, Val⁹³, Lys⁹⁴, Glu⁹⁵, His⁹⁶, Ile⁹⁹, Tyr¹⁰⁰, Ile¹⁰³ according to Table 1 or Table 2 or similar structure coordinates for said amino acids comprising a root mean square deviation of non-hydrogen atoms of less than about 1.5 Å when superimposed on the non-hydrogen atom positions of the corresponding atomic coordinates of Table 1 or Table 2. In a highly preferred embodiment, the agent is exposed to crystalline SEQ ID NO:2 and the detecting of step (b) comprises determining the three dimensional structure of the agent-SEQ ID NO: 2 complex.

The invention further includes a method of evaluating the potential of an agent to associate with the peptide having aa¹⁶-SEQ ID NO: 2, comprising: (a) exposing aa¹⁶-SEQ ID NO: 2 to the agent; and (b) detecting the level of association of the agent to aa¹⁶-SEQ ID NO: 2, thereby evaluating the potential. In one embodiment, the agent is a virtual compound.

The present invention includes a method of identifying a potential agonist or antagonist against HDM2 comprising: (a) employing the three dimensional structure of HDM2 cocrystallized with a small molecule inhibitor to design or select said potential agonist or antagonist. In one embodiment, the three dimensional structure corresponds to the atomic structure characterized by the coordinates of Table 1 or similar structure coordinates comprising a root mean square deviation of non-hydrogen atoms of less than about 1.5 Å when superimposed on the non-hydrogen atom positions of the corresponding atomic coordinates of Table 1 or Table 2. In a different embodiment, the method further comprises the steps of: (b) synthesizing the potential agonist or antagonist; and (c) contacting the potential agonist or antagonist with HDM2.

The instant invention comprises a method of locating the attachment site of an inhibitor to HDM2, comprising: (a) obtaining X-ray diffraction data for a crystal of HDM2; (b) obtaining X-ray diffraction data for a complex of HDM2 and an inhibitor; (c) subtracting the X-ray diffraction data obtained in step (a) from the X-ray diffraction data obtained in step (b) to obtain the difference in the X-ray diffraction data; (d) obtaining phases that correspond to X-ray diffraction data obtained in step (a); (e) utilizing the phases obtained in step (d) and the difference in the X-ray diffraction data obtained in step (c) to compute a difference Fourier image of the inhibitor; and, (f) locating the attachment site of the inhibitor to HDM2 based on the computations obtained in step (e).

The present invention further comprises a method of obtaining a modified inhibitor comprising: (a) obtaining a crystal comprising HDM2 and an inhibitor; (b) obtaining the atomic coordinates of the crystal; (c) using the atomic coordinates and one or more molecular modeling techniques to determine how to modify the interaction of the inhibitor with HDM2; and, (d) modifying the inhibitor based on the determinations obtained in step (c) to produce a modified inhibitor. In one embodiment, the crystal comprises a peptide selected from the group consisting of: a peptide having SEQ ID NO: 2; a peptide having SEQ ID NO: 3 and a peptide having SEQ ID NO:4. In a different embodiment, the one or more molecular modeling techniques are selected from the group consisting of graphic molecular modeling and computational chemistry. In a preferred embodiment, step (a) comprises detecting the interaction of the inhibitor to HDM2 amino acid residues Ser¹⁷, Ile¹⁹, Leu⁸² and Arg⁹⁷. In another embodiment of the invention, the invention includes an HDM2 inhibitor identified by this method.

In another aspect of the invention, the invention includes an isolated protein fragment comprising a binding pocket or active site defined by structure coordinates of HDM2 amino acid residues Ser¹⁷, Ile¹⁹, Leu⁸² and Arg⁹⁷. In one embodiment, the isolated fragment is linked to a solid support.

In another aspect of the invention, the invention includes an isolated nucleic acid molecule encoding the fragment which comprises a binding pocket or active site defined by structure coordinates of HDM2 amino acid residues Ser¹⁷, Ile¹⁹, Leu⁸² and Arg⁹⁷. In one embodiment, a vector comprises the nucleic acid molecule. In another embodiment, a host cell comprises the vector. In yet another aspect of the invention, the invention includes a method of producing a protein fragment, comprising culturing the host cell under conditions in which the fragment is expressed. In another aspect of the invention, the invention includes a method of screening for an agent that associates with HDM2, comprising: (a) exposing a protein molecule fragment to the agent; and (b) detecting the level of association of the agent to the fragment. In another aspect of the invention, the invention includes a kit comprising a protein molecule fragment.

In another aspect of the invention, the invention includes a method for the production of a crystal complex comprising an HDM2 polypeptide-ligand comprising: (a) contacting the HDM2 polypeptide with said ligand in a suitable solution comprising PEG and NaSCN; and, b) crystallizing said resulting complex of HDM2 polypeptide-ligand from said solution. In one embodiment, the HDM2 polypeptide is a polypeptide having SEQ ID NO: 2. In another embodiment, PEG has an average molecular weight range from 100 to 1000, wherein said PEG is present in solution at a range from about 0.5% w/v to about 10% w/v and said NaSCN is present in solution at a range of from about 50 mM to about 150 mM. In a preferred embodiment, PEG has an average molecular weight of about 400 and is present in solution at about 2% w/v and said NaSCN is present in solution at about 100 mM. In a highly preferred embodiment, the solution further comprises about 1.8-2.4 M (NH₄)₂SO₄ and about 100 mM buffer.

The invention further includes a method for the production of a crystal comprising HDM2 and a ligand wherein the ligand is a small molecule inhibitor comprising crystallizing a peptide comprising a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO:4 with a potential inhibitor.

The invention includes a method for identifying a potential inhibitor of HDM2 comprising: a) using a three dimensional structure of HDM2 as defined by atomic coordinates according to table 1; b) replacing one or more HDM2 amino acids selected from Ser¹⁷, Ile¹⁹, Leu⁸² and Arg⁹⁷ in said three-dimensional structure with a different amino acid to produce a modified HDM2; c) using said three-dimensional structure to design or select said potential inhibitor; d) synthesizing said potential inhibitor; and, e) contacting said potential inhibitor with said modified HDM2 in the presence of a substrate to test the ability of said potential inhibitor to inhibit HDM2 or said modified HDM2. In one embodiment, replacing one or more amino acid residues further comprises replacing SEQ ID NO: 2 amino acids selected from the group consisting of Val⁵³, Leu⁵⁴, Phe⁵⁵, Leu⁵⁷, Gly⁵⁸, Gln⁵⁹, Ile⁶¹, Met⁶², Tyr⁶⁷, Gln⁷², His⁷³, Ile⁷⁴, Val⁷⁵, Phe⁸⁶, Phe⁹¹, Val⁹³, Lys⁹⁴, Glu⁹⁵, His⁹⁶, Ile⁹⁹, Tyr¹⁰⁰, and Ile¹⁰³. In another embodiment, the potential inhibitor is selected from a database. In a preferred embodiment, the potential inhibitor is designed de novo. In another preferred embodiment, the potential inhibitor is designed from a known inhibitor. In a highly preferred embodiment, the step of employing said three-dimensional structure to design or select said potential inhibitor comprises the steps of: a) identifying chemical entities or fragments capable of associating with modified HDM2; and b) assembling the identified chemical entities or fragments into a single molecule to provide the structure of said potential inhibitor. In one embodiment, the potential inhibitor is a competitive inhibitor of SEQ ID NO:4 (Gly¹⁶-SEQ ID NO: 2). In a different embodiment, the potential inhibitor is a non-competitive or uncompetitive inhibitor of SEQ ID NO:4 (Gly¹⁶-SEQ ID NO: 2). In yet another embodiment, an inhibitor is identified by the method.

A. Modeling the Three-Dimensional Structure of HDM2

The atomic coordinate data provided in Table 1, Table 2 or the coordinate data derived from homologous proteins may be used to build a three-dimensional model of HDM2. Any available computational methods may be used to build the three dimensional model. As a starting point, the X-ray diffraction pattern obtained from the assemblage of the molecules or atoms in a crystalline version of HDM2 or an HDM2 homolog can be used to build an electron density map using tools well known to those skilled in the art of crystallography and X-ray diffraction techniques. Additional phase information extracted either from the diffraction data and available in the published literature and/or from supplementing experiments may then used to complete the reconstruction.

For basic concepts and procedures of collecting, analyzing, and utilizing X-ray diffraction data for the construction of electron densities see, for example, Campbell et al., 1984, Biological Spectroscopy, The Benjamin/Cummings Publishing Co., Inc., Menlo Park, Calif.; Cantor et al., 1980, Biophysical Chemistry, Part II: Techniques for the study of biological structure and function, W.H. Freeman and Co., San Francisco, Calif.; A. T. Brunger, 1993, X-Flor Version 3.1: A system for X-ray crystallography and NMR, Yale Univ. Pr., New Haven, Conn.; M. M. Woolfson, 1997, An Introduction to X-ray Crystallography, Cambridge Univ. Pr., Cambridge, UK; J. Drenth, 1999, Principles of Protein X-ray Crystallography (Springer Advanced Texts in Chemistry), Springer Verlag; Berlin; Tsirelson et al., 1996, Electron Density and Bonding in Crystals: Principles, Theory and X-ray Diffraction Experiments in Solid State Physics and Chemistry, Inst. of Physics Pub.; U.S. Pat. No. 5,942,428; U.S. Pat. No. 6,037,117; U.S. Pat. No. 5,200,910 and U.S. Pat. No. 5,365,456 (“Method for Modeling the Electron Density of a Crystal”), each of which is herein specifically incorporated by reference in their entirety.

For basic information on molecular modeling, see, for example, M. Schlecht, Molecular Modeling on the PC, 1998, John Wiley & Sons; Gans et al., Fundamental Principals of Molecular Modeling, 1996, Plenum Pub. Corp.; N. C. Cohen (editor), Guidebook on Molecular Modeling in Drug Design, 1996, Academic Press; and W. B. Smith, Introduction to Theoretical Organic Chemistry and Molecular Modeling, 1996. U.S. patents which provide detailed information on molecular modeling include U.S. Pat. Nos. 6,093,573; 6,080,576; 6,075,014; 6,075,123; 6,071,700; 5,994,503; 5,612,894; 5,583,973; 5,030,103; 4,906,122; and 4,812,12, each of which are incorporated by reference herein in their entirety.

B. Methods of Using the Atomic Coordinates to Identify and Design Ligands of Interest

The atomic coordinates of the invention, such as those described in Table 1, Table 2, Table 3 or coordinates substantially identical to or homologous to those of Table 1, Table 2, or Table 3 may be used with any available methods to prepare three dimensional models of HDM2 as well as to identify and design HDM2 ligands, inhibitors or antagonists or agonist molecules.

For instance, three-dimensional modeling may be performed using the experimentally determined coordinates derived from X-ray diffraction patterns, such as those in Table 1 or Table 2, for example, wherein such modeling includes, but is not limited to, drawing pictures of the actual structures, building physical models of the actual structures, and determining the structures of related subunits and HDM2/ligand and HDM2 subunit/ligand complexes using the coordinates. Such molecular modeling can utilize known X-ray diffraction molecular modeling algorithms or molecular modeling software to generate atomic coordinates corresponding to the three-dimensional structure of HDM2.

As described above, molecular modeling involves the use of computational methods, preferably computer assisted methods, to build realistic models of molecules that are identifiably related in sequence to the known crystal structure. It also involves modeling new small molecule inhibitors bound to HDM2 starting with the structures of HDM2 and or HDM2 complexed with known ligands or inhibitors. The methods utilized in ligand modeling range from molecular graphics (i.e., 3D representations) to computational chemistry (i.e., calculations of the physical and chemical properties) to make predictions about the binding of ligands or activities of ligands; to design new ligands; and to predict novel molecules, including ligands such as drugs, for chemical synthesis, collectively referred to as rational drug design.

One approach to rational drug design is to search for known molecular structures that might bind to an active site. Using molecular modeling, rational drug design programs can look at a range of different molecular structures of drugs that may fit into the active site of an enzyme, and by moving them in a three-dimensional environment it can be decided which structures actually fit the site well. See, for example, U.S. Appl. Nos. 60/275,629; 60/331,235; 60/379,617; and, Ser. No. 10/097,249. See, also, for example, data in Tables 1, 2 and 3.

An alternative but related rational drug design approach starts with the known structure of a complex with a small molecule ligand and models modifications of that small molecule in an effort to make additional favorable interactions with HDM2.

The present invention include the use of molecular and computer modeling techniques to design and select and design ligands, such as small molecule agonists or antagonists or other therapeutic agents that interact with HDM2. Such agents include, but are not limited to 1,4 benzodiazepines and derivatives thereof. For example, the invention as herein described includes the design of ligands that act as competitive inhibitors of at least one HDM2 function by binding to all, or a portion of, the active sites or other regions of HDM2.

This invention also includes the design of compounds that act as uncompetitive inhibitors of at least one function of HDM2. These inhibitors may bind to all, or a portion of, the active sites or other regions of HDM2 already bound to its substrate and may be more potent and less non-specific than competitive inhibitors that compete for HDM2 active sites. Similarly, non-competitive inhibitors that bind to and inhibit at least one function of HDM2 whether or not it is bound to another chemical entity may be designed using the atomic coordinates of HDM2 or complexes comprising HDM2 of this invention.

The atomic coordinates of the present invention also provide the needed information to probe a crystal of HDM2 with molecules composed of a variety of different chemical features to determine optimal sites for interaction between candidate inhibitors and/or activators and HDM2. For example, high resolution X-ray diffraction data collected from crystals saturated with solvent allows the determination of where each type of solvent molecule sticks. Small molecules that bind to those sites can then be designed and synthesized and tested for their inhibitory activity (Travis, J., Science 262:1374 (1993)).

The present invention also includes methods for computationally screening small molecule databases and libraries for chemical entities, agents, ligands, or compounds that can bind in whole, or in part, to HDM2. In this screening, the quality of fit of such entities or compounds to the binding site or sites may be judged either by shape complementarity or by estimated interaction energy (Meng, E. C. et al., J. Coma. Chem. 13:505-524 (1992)).

The design of compounds that bind to promote or inhibit the functional activity of HDM2 according to this invention generally involves consideration of two factors. First, the compound must be capable of physically and structurally associating with HDM2. Non-covalent molecular interactions important in the association of HDM2 with the compound, include hydrogen bonding, van der Waals and hydrophobic interactions. Second, the compound must be able to assume a conformation that allows it to associate with HDM2. Although certain portions of the compound may not directly participate in the association with HDM2, those portions may still influence the overall conformation of the molecule. This, in turn, may have a significant impact on binding affinities, therapeutic efficacy, drug-like qualities and potency. Such conformational requirements include the overall three-dimensional structure and orientation of the chemical entity or compound in relation to all or a portion of the active site or other region of HDM2, or the spacing between functional groups of a compound comprising several chemical entities that directly interact with HDM2.

The potential, predicted, inhibitory agonist, antagonist or binding effect of a ligand or other compound on HDM2 may be analyzed prior to its actual synthesis and testing by the use of computer modeling techniques. If the theoretical structure of the given compound suggests insufficient interaction and association between it and HDM2, synthesis and testing of the compound may be obviated. However, if computer modeling indicates a strong interaction, the molecule may then be synthesized and tested for its ability to interact with HDM2. In this manner, synthesis of inoperative compounds may be avoided. In some cases, inactive compounds are synthesized predicted on modeling and then tested to develop a SAR (structure-activity relationship) for compounds interacting with a specific region of HDM2.

One skilled in the art may use one of several methods to screen chemical entities fragments, compounds, or agents for their ability to associate with HDM2 and more particularly with the individual binding pockets or active sites of HDM2. This process may begin by visual inspection of, for example, the active site on the computer screen based on the atomic coordinates of HDM2 or HDM2 complexed with a ligand. Selected chemical entities, compounds, or agents may then be positioned in a variety of orientations, or docked within an individual binding pocket of HDM2. Docking may be accomplished using software such as Quanta and Sybyl, followed by energy minimization and molecular dynamics with standard molecular mechanics forcefields, such as CHARMM and AMBER.

Specialized computer programs may also assist in the process of selecting chemical entities. These include but are not limited to: GRID (Goodford, P. J., “A Computational Procedure for Determining Energetically Favorable Binding Sites on Biologically Important Macromolecules,” J. Med. Chem. 28:849-857 (1985), available from Oxford University, Oxford, UK); MCSS (Miranker, A. and M. Karplus, “Functionality Maps of Binding Sites: A Multiple Copy Simultaneous Search Method.” Proteins: Structure, Function and Genetics 11: 29-34 (1991), available from Molecular Simulations, Burlington, Mass.); AUTODOCK (Goodsell, D. S, and A. J. Olsen, “Automated Docking of Substrates to Proteins by Simulated Annealing” Proteins: Structure. Function, and Genetics 8:195-202 (1990), available from Scripps Research Institute, La Jolla, Calif.); and DOCK (Kuntz, I. D. et al., “A Geometric Approach to Macromolecule-Ligand Interactions,” J. Mol. Biol. 161:269-288 (1982), available from University of California, San Francisco, Calif.).

The use of software such as GRID, a program that determines probable interaction sites between probes with various functional group characteristics and the macromolecular surface, is used to analyze the surface sites to determine structures of similar inhibiting proteins or compounds. The GRID calculations, with suitable inhibiting groups on molecules (e.g. protonated primary amines) as the probe, are used to identify potential hotspots around accessible positions at suitable energy contour levels. The program DOCK may be used to analyze an active site or ligand binding site and suggest ligands with complementary steric properties.

Once suitable chemical entities, compounds, or agents have been selected, they can be assembled into a single ligand or compound or inhibitor or activator. Assembly may proceed by visual inspection of the relationship of the fragments to each other on the three-dimensional image. This may be followed by manual model building using software such as Quanta or Sybyl.

Useful programs to aid in connecting the individual chemical entities, compounds, or agents include but are not limited to: CAVEAT (Bartlett, P. A. et al., “CAVEAT: A Program to Facilitate the Structure-Derived Design of Biologically Active Molecules.” In Molecular Recognition in Chemical and Biological Problems, Special Pub., Royal Chem. Soc., 78, pp. 82-196 (1989)); 3D Database systems such as MACCS-3D (MDL Information Systems, San Leandro, Calif. and Martin, Y. C., “3D Database Searching in Drug Design”, J. Med. Chem. 35: 2145-2154 (1992); and HOOK (available from Molecular Simulations, Burlington, Mass.).

Several methodologies for searching three-dimensional databases to test pharmacophore hypotheses and select compounds for screening are available. These include the program CAVEAT (Bacon et al., J. Mol. Biol. 225:849-858 (1992)). For instance, CAVEAT uses databases of cyclic compounds which can act as “spacers” to connect any number of chemical fragments already positioned in the active site. This allows one skilled in the art to quickly generate hundreds of possible ways to connect the fragments already known or suspected to be necessary for tight binding.

Instead of proceeding to build an inhibitor activator, agonist or antagonist of HDM2 in a step-wise fashion one chemical entity at a time as described above, such compounds may be designed as a whole or “de novo” using either an empty active site or optionally including some portion(s) of a known molecules. These methods include: LUDI (Bohm, H.-J., “The Computer Program LUDI: A New Method for the De Novo Design of Enzyme Inhibitors”, J. ComR. Aid. Molec. Design, 6, pp. 61-78 (1992), available from Biosym Technologies, San Diego, Calif.); LEGEND (Nishibata, Y. and A. Itai, Tetrahedron 47:8985 (1991), available from Molecular Simulations, Burlington, Mass.); and LeapFrog (available from Tripos Associates, St. Louis, Mo.).

For instance, the program LUDI can determine a list of interaction sites into which to place both hydrogen bonding and hydrophobic fragments. LUDI then uses a library of linkers to connect up to four different interaction sites into fragments. Then smaller “bridging” groups such as —CH2- and —COO— are used to connect these fragments. For example, for the enzyme DHFR, the placements of key functional groups in the well-known inhibitor methotrexate were reproduced by LUDI. See also, Rotstein and Murcko, J. Med. Chem. 36: 1700-1710 (1992).

Other molecular modeling techniques may also be employed in accordance with this invention. See, e.g., Cohen, N. C. et al, “Molecular Modeling Software and Methods for Medicinal Chemistry, J. Med. Chem. 33:883-894 (1990). See also, Navia, M. A. and M. A. Murcko, “The Use of Structural Information in Drug Design,” Current Opinions in Structural Biology, 2, pp. 202-210 (1992).

Once a compound has been designed or selected by the above methods, the affinity with which that compound may bind or associate with HDM2 may be tested and optimized by computational evaluation and/or by testing biological activity after synthesizing the compound. Inhibitors or compounds may interact with the HDM2 in more than one conformation that is similar in overall binding energy. In those cases, the deformation energy of binding is taken to be the difference between the energy of the free compound and the average energy of the conformations observed when the compound binds to HDM2.

A compound designed or selected as binding or associating with HDM2 may be further computationally optimized so that in its bound state it would preferably lack repulsive electrostatic interaction with HDM2. Such non-complementary (e.g., electrostatic) interactions include repulsive charge-charge, dipole-dipole and charge-dipole interactions. Specifically, the sum of all electrostatic interactions between the inhibitor and HDM2 when the inhibitor is bound, preferably make a neutral or favorable contribution to the enthalpy of binding. Weak binding compounds will also be designed by these methods so as to determine SAR. See, for example, U.S. Appl. Nos. 60/275,629; 60/331,235; 60/379,617; and, Ser. No. 10/097,249.

Specific computer software is available in the art to evaluate compound deformation energy and electrostatic interaction. Examples of programs designed for such uses include: Gaussian 92, revision C (M. J. Frisch, Gaussian, Inc., Pittsburgh, Pa., COPYRGT 1992); AMBER, version 4.0 (P. A. Kollman, University of California at San Francisco, COPYRGT 1994); QUANTA/CHARMM (Molecular Simulations, Inc., Burlington, Mass. COPYRGT 1994); and Insight II/Discover (Biosysm Technologies Inc., San Diego, Calif. COPYRGT 1994). Other hardware systems and software packages will be known to those skilled in the art.

Once a compound that associates with HDM2 has been optimally selected or designed, as described above, substitutions may then be made in some of its atoms or side groups in order to improve or modify its binding properties. Generally, initial substitutions are conservative, i.e., the replacement group will have approximately the same size, shape, hydrophobicity and charge as the original group. It should, of course, be understood that components known in the art to alter conformation may be avoided. Such substituted chemical compounds may then be analyzed for efficiency of fit to HDM2 by the same computer methods described in detail, above.

C. Use of Homology Structure Modeling to Design Ligands with Modulated Binding or Activity to HDM2

The present invention includes the use of the atomic coordinates and structures of HDM2 and/or HDM2 complexed with an inhibitor to design modifications to starting compounds, such as (4-Choloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid; [8-Chloro-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid; and derivatives thereof that will bind more tightly or interact more specifically to the target enzyme. See, U.S. Appl. Nos. 60/275,629; 60/331,235; 60/379,617; and, Ser. No. 10/097,249, disclosing compounds 1 and 2 and derivatives thereof, all of which are incorporated herein in their entirety.

Compound 1 (338437): (4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid

Compound 2 (876273): [8-Chloro-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid

The structure of a complex between the HDM2 and the starting compound can be used to guide the modification of that compound to produce new compounds that have other desirable properties for applicable industrial and other uses (e.g., as pharmaceuticals), such as chemical stability, solubility or membrane permeability. (Lipinski et al., Adv. Drug Deliv. Rev. 23:3 (1997)).

Binding compounds, agonists, antagonists and such that are known in the art include but are not limited to p53 peptides and small molecule antagonists. See, for example, U.S. Appl. Nos. 60/275,629; 60/331,235; 60/379,617; and, Ser. No. 10/097,249 incorporated by reference herein in their entirety. Such compounds can be diffused into or soaked with the stabilized crystals of HDM2 to form a complex for collecting X-ray diffraction data. Alternatively, the compounds, known and unknown in the art, can be cocrystallized with HDM2 by mixing the compound with HDM2 before precipitation.

To produce custom high affinity and very specific compounds, the structure of HDM2 can be compared to the structure of a selected non-targeted molecule and a hybrid constructed by changing the structure of residues at the binding site for a ligand for the residues at the same positions of the non-target molecule. The process whereby this modeling is achieved is referred to as homology structure modeling. This is done computationally by removing the side chains from the molecule or target of known structure and replacing them with the side chains of the unknown structure put in sterically plausible positions. In this way it can be understood how the shapes of the active site cavities of the targeted and non-targeted molecules differ. This process, therefore, provides information concerning how a bound ligand can be chemically altered in order to produce compounds that will bind tightly and specifically to the desired target but will simultaneously be sterically prevented from binding to the non-targeted molecule. Likewise, knowledge of portions of the bound ligands that are facing to the solvent would allow introduction of other functional groups for additional pharmaceutical purposes. The use of homology structure modeling to design molecules (ligands) that bind more tightly to the target enzyme than to the non-target enzyme has wide spread applicability.

D. High Throughput Assays

Any high throughput screening may be utilized to test new compounds which are identified or designed for their ability to interact with HDM2. For general information on high-throughput screening see, for example, Devlin, 1998, High Throughput Screening, Marcel Dekker; and U.S. Pat. No. 5,763,263. High throughput assays utilize one or more different assay techniques including, but not limited to, those described below.

Immunodiagnostics and Immunoassays. These are a group of techniques used for the measurement of specific biochemical substances, commonly at low concentrations in complex mixtures such as biological fluids, that depend upon the specificity and high affinity shown by suitably prepared and selected antibodies for their complementary antigens. A substance to be measured must, of necessity, be antigenic—either an immunogenic macromolecule or a haptenic small molecule. To each sample a known, limited amount of specific antibody is added and the fraction of the antigen combining with it, often expressed as the bound:free ratio, is estimated, using as indicator a form of the antigen labeled with radioisotope (radioimmunoassay), fluorescent molecule (fluoroimmunoassay), stable free radical (spin immunoassay), enzyme (enzyme immunoassay), or other readily distinguishable label.

Antibodies can be labeled in various ways, including: enzyme-linked immunosorbent assay (ELISA); radioimmuno assay (RIA); fluorescent immunoassay (FIA); chemiluminescent immunoassay (CLIA); and labeling the antibody with colloidal gold particles (immunogold).

Common assay formats include the sandwich assay, competitive or competition assay, latex agglutination assay, homogeneous assay, microtitre plate format and the microparticle-based assay.

Enzyme-linked immunosorbent assay (ELISA). ELISA is an immunochemical technique that avoids the hazards of radiochemicals and the expense of fluorescence detection systems. Instead, the assay uses enzymes as indicators. ELISA is a form of quantitative immunoassay based on the use of antibodies (or antigens) that are linked to an insoluble carrier surface, which is then used to “capture” the relevant antigen (or antibody) in the test solution. The antigen-antibody complex is then detected by measuring the activity of an appropriate enzyme that had previously been covalently attached to the antigen (or antibody).

For information on ELISA techniques, see, for example, Crowther, (1995) ELISA—Theory and Practice (Methods in Molecular Biology), Humana Press; Challacombe & Kemeny, (1998) ELISA and Other Solid Phase Immunoassays—Theoretical and Practical Aspects, John Wiley; Kemeny, (1991) A Practical Guide to ELISA, Pergamon Press; Ishikawa, (1991) Ultrasensitive and Rapid Enzyme Immunoassay (Laboratory Techniques in Biochemistry and Molecular Biology) Elsevier.

Colorimetric Assays for Enzymes. Colorimetry is any method of quantitative chemical analysis in which the concentration or amount of a compound is determined by comparing the color produced by the reaction of a reagent with both standard and test amounts of the compound, often using a colorimeter. A calorimeter is a device for measuring color intensity or differences in color intensity, either visually or photoelectrically.

Standard colorimetric assays of beta-galactosidase enzymatic activity are well known to those skilled in the art (see, for example, Norton et al., Mol. Cell. Biol. 5:281-290 (1985). A colorimetric assay can be performed on whole cell lysates using O-nitrophenyl-beta-D-galactopyranoside (ONPG, Sigma) as the substrate in a standard colorimetric beta-galactosidase assay (Sambrook et al., (1989) Molecular Cloning—A Laboratory Manual, Cold Spring Harbor Laboratory Press). Automated calorimetric assays are also available for the detection of beta-galactosidase activity, as described in U.S. Pat. No. 5,733,720.

Immunofluorescence Assays. Immunofluorescence or immunofluorescence microscopy is a technique in which an antigen or antibody is made fluorescent by conjugation to a fluorescent dye and then allowed to react with the complementary antibody or antigen in a tissue section or smear. The location of the antigen or antibody can then be determined by observing the fluorescence by microscopy under ultraviolet light.

For general information on immunofluorescent techniques, see, for example, Knapp et al., (1978) Immunofluorescence and Related Staining Techniques, Elsevier; Allan, (1999) Protein Localization by Fluorescent Microscopy—A Practical Approach (The Practical Approach Series) Oxford University Press; Caul, (1993) Immunofluorescence Antigen Detection Techniques in Diagnostic Microbiology, Cambridge University Press. For detailed explanations of immunofluorescent techniques applicable to the present invention, see U.S. Pat. No. 5,912,176; U.S. Pat. No. 5,869,264; U.S. Pat. No. 5,866,319; and U.S. Pat. No. 5,861,259.

E. Databases and Computer Systems

An amino acid sequence or nucleotide sequence of HDM2 and/or X-ray diffraction data, useful for computer molecular modeling of HDM2 or a portion thereof, can be “provided” in a variety of mediums to facilitate use thereof. As used herein, “provided” refers to a manufacture, which contains, for example, an amino acid sequence or nucleotide sequence and/or atomic coordinates derived from X-ray diffraction data of the present invention, e.g. an amino acid or nucleotide sequence of HDM2, a representative fragment thereof, or a homologue thereof. Such a method provides the amino acid sequence and/or X-ray diffraction data in a form which allows a skilled artisan to analyze and molecular model the three-dimensional structure of HDM2 or related molecules, including a subdomain thereof.

In one application of this embodiment, databases comprising data pertaining to HDM2, or at least one subdomain thereof, amino acid and nucleic acid sequence and/or X-ray diffraction data of the present invention is recorded on computer readable medium. As used herein, “computer readable medium” refers to any medium which can be read and accessed directly by a computer. Such media include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage media, and magnetic tape; optical storage media such as optical discs or CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media. A skilled artisan can readily appreciate how any of the presently known computer readable media can be used to create a manufacture comprising computer readable medium having recorded thereon an amino acid sequence and/or X-ray diffraction data of the present invention.

As used herein, “recorded” refers to a process for storing information on computer readable media. A skilled artisan can readily adopt any of the presently known methods for recording information on computer readable media to generate manufactures comprising an amino acid sequence and/or atomic coordinate/X-ray diffraction data information of the present invention.

A variety of data storage structures are available to a skilled artisan for creating a computer readable medium having recorded thereon an amino acid sequence and/or atomic coordinate/X-ray diffraction data of the present invention. The choice of the data storage structure will generally be based on the means chosen to access the stored information. In addition, a variety of data processor programs and formats can be used to store the sequence and X-ray data information of the present invention on computer readable media. The sequence information can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and MICROSOFT Word, or represented in the form of an ASCII file, stored in a database application, such as DB2, Sybase, Oracle, or the like. A skilled artisan can readily adapt any number of dataprocessor structuring formats (e.g. text file or database) in order to obtain computer readable media having recorded thereon the information of the present invention.

By providing computer readable media having sequence and/or atomic coordinates based on X-ray diffraction data, a skilled artisan can routinely access the sequence and atomic coordinate or X-ray diffraction data to model a related molecule, a subdomain, mimetic, or a ligand thereof. Computer algorithms are publicly and commercially available which allow a skilled artisan to access this data provided in a computer readable medium and analyze it for molecular modeling and/or RDD (rational drug design). See, e.g., Biotechnology Software Directory, MaryAnn Liebert Publ., New York (1995).

The present invention further provides systems, particularly computer-based systems, which contain the sequence and/or diffraction data described herein. Such systems are designed to do structure determination and RDD for HDM2 or at least one subdomain thereof. Non-limiting examples are microcomputer workstations available from Silicon Graphics Incorporated and Sun Microsystems running UNIX based, Windows NT or IBM OS/2 operating systems.

As used herein, “a computer-based system” refers to the hardware means, software means, and data storage means used to analyze the sequence and/or X-ray diffraction data of the present invention. The minimum hardware means of the computer-based systems of the present invention comprises a central processing unit (CPU), input means, output means, and data storage means. A skilled artisan can readily appreciate which of the currently available computer-based systems are suitable for use in the present invention. A visualization device, such as a monitor, is optionally provided to visualize structure data.

As stated above, the computer-based systems of the present invention comprise a data storage means having stored therein sequence and/or atomic coordinate/X-ray diffraction data of the present invention and the necessary hardware means and software means for supporting and implementing an analysis means. As used herein, “data storage means” refers to memory which can store sequence or atomic coordinate/X-ray diffraction data of the present invention, or a memory access means which can access manufactures having recorded thereon the sequence or X-ray data of the present invention.

As used herein, “search means” or “analysis means” refers to one or more programs which are implemented on the computer-based system to compare a target sequence or target structural motif with the sequence or X-ray data stored within the data storage means. Search means are used to identify fragments or regions of a protein which match a particular target sequence or target motif A variety of known algorithms are disclosed publicly and a variety of commercially available software for conducting search means are and can be used in the computer-based systems of the present invention. A skilled artisan can readily recognize that any one of the available algorithms or implementing software packages for conducting computer analyses can be adapted for use in the present computer-based systems.

As used herein, “a target structural motif,” or “target motif,” refers to any rationally selected sequence or combination of sequences in which the sequence(s) are chosen based on a three-dimensional configuration or electron density map which is formed upon the folding of the target motif. There are a variety of target motifs known in the art. Protein target motifs include, but are not limited to, enzymatic active sites, inhibitor binding sites, structural subdomains, epitopes, functional domains and signal sequences. Similar motifs are known for RNA. A variety of structural formats for the input and output means can be used to input and output the information in the computer-based systems of the present invention.

A variety of comparing means can be used to compare a target sequence or target motif with the data storage means to identify structural motifs or electron density maps derived in part from the atomic coordinate/X-ray diffraction data. A skilled artisan can readily recognize that any one of the publicly available computer modeling programs can be used as the search means for the computer-based systems of the present invention.

F. Target Molecule Fragments and Portions

Fragments of HDM2, for instance fragments comprising active sites defined by two or more amino acids selected from the group consisting of: Ser¹⁷, Ile¹⁹, Leu⁸² and Arg⁹⁷, may be prepared by any available means including synthetic or recombinant means. Such fragments may then be used in the assays as described above, for instance, high through-put assays to detect interactions between prospective agents and the active site within the fragment.

For recombinant expression or production of the fragments of the invention, nucleic acid molecules encoding the fragment may be prepared. As used herein, “nucleic acid” is defined as RNA or DNA that encodes a protein or peptide as defined above, or is complementary to nucleic acid sequence encoding such peptides, or hybridizes to such nucleic acid and remains stably bound to it under appropriate stringency conditions.

Nucleic acid molecules encoding fragments of the invention may differ in sequence because of the degeneracy in the genetic code or may differ in sequence as they encode proteins or protein fragments that differ in amino acid sequence. Homology or sequence identity between two or more such nucleic acid molecules is determined by BLAST (Basic Local Alignment Search Tool) analysis using the algorithm employed by the programs blastp, blastn, blastx, tblastn and tblastx (Karlin et al., Proc. Natl. Acad. Sci. USA 87:2264-2268 (1990) and Altschul, et al., J. Mol. Evol. 36:290-300 (1993), fully incorporated by reference) which are tailored for sequence similarity searching.

The approach used by the BLAST program is to first consider similar segments between a query sequence and a database sequence, then to evaluate the statistical significance of all matches that are identified and finally to summarize only those matches which satisfy a preselected threshold of significance. For a discussion of basic issues in similarity searching of sequence databases, see Altschul et al. (Nat. Genet. 6, 119-129 (1994)) which is fully incorporated by reference. The search parameters for histogram, descriptions, alignments, expect (i.e., the statistical significance threshold for reporting matches against database sequences), cutoff, matrix and filter are at the default settings. The default scoring matrix used by blastp, blastx, tblastn, and tblastx is the BLOSUM62 matrix (Henikoff et al., Proc. Natl. Acad. Sci. USA 89:10915-10919 (1992), fully incorporated by reference). Four blastn parameters were adjusted as follows: Q=10 (gap creation penalty); R=10 (gap extension penalty); wink=1 (generates word hits at every wink^(th) position along the query); and gapw=16 (sets the window width within which gapped alignments are generated). The equivalent Blastp parameter settings were Q=9; R=2; wink=1; and gapw=32. A Bestfit comparison between sequences, available in the GCG package version 10.0, uses DNA parameters GAP=50 (gap creation penalty) and LEN=3 (gap extension penalty) and the equivalent settings in protein comparisons are GAP=8 and LEN=2.

“Stringent conditions” are those that (1) employ low ionic strength and high temperature for washing, for example, 0.015 M NaCl/0.0015 M sodium citrate/0.1% SDS at 50° C. or (2) employ during hybridization a denaturing agent such as formamide, for example, 50% formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM NaCl, 75 mM sodium citrate at 42° C. Another example is use of 50% formamide, 5×SSC, 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5×Denhardt's solution, sonicated salmon sperm DNA (50 mg/ml), 0.1% SDS and 10% dextran sulfate at 42° C., with washes at 42° C. in 0.2×SSC and 0.1% SDS. A skilled artisan can readily determine and vary the stringency conditions appropriately to obtain a clear and detectable hybridization signal.

As used herein, a nucleic acid molecule is said to be “isolated” when the nucleic acid molecule is substantially separated from contaminant nucleic acid encoding other polypeptides from the source of nucleic acid.

The encoding nucleic acid molecules of the present invention (i.e., synthetic oligonucleotides) and those that are used as probes or specific primers for polymerase chain reaction (PCR) or to synthesize gene sequences encoding proteins of the invention can easily be synthesized by chemical techniques, for example, the phosphotriester method of Matteucci et al. (J. Am. Chem. Soc. 103: 185-3191 (1981)) or using automated synthesis methods. In addition, larger DNA segments can readily be prepared by well known methods, such as synthesis of a group of oligonucleotides that define various modular segments of the gene, followed by ligation of oligonucleotides to build the complete modified gene.

The encoding nucleic acid molecules of the present invention may further be modified so as to contain a detectable label for diagnostic and probe purposes. A variety of such labels are known in the art and can readily be employed with the encoding molecules herein described. Suitable labels include, but are not limited to, biotin, radiolabeled nucleotides and the like. A skilled artisan can employ any of the art-known labels to obtain a labeled encoding nucleic acid molecule.

The present invention further provides recombinant DNA molecules (rDNA) that contain a coding sequence for a protein fragment as described above. As used herein, a rDNA molecule is a DNA molecule that has been subjected to molecular manipulation. Methods for generating rDNA molecules are well known in the art, for example, see Sambrook et al. Molecular Cloning—A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989). In the preferred rDNA molecules, a coding DNA sequence is operably linked to expression control sequences and/or vector sequences.

The choice of vector and expression control sequences to which one of the protein encoding sequences of the present invention is operably linked depends directly, as is well known in the art, on the functional properties desired (e.g., protein expression, and the host cell to be transformed). A vector of the present invention may be capable of directing the replication or insertion into the host chromosome, and preferably also expression, of the structural gene included in the rDNA molecule. Expression control elements that are used for regulating the expression of an operably linked protein encoding sequence are known in the art and include, but are not limited to, inducible promoters, constitutive promoters, secretion signals, and other regulatory elements. Preferably, the inducible promoter is readily controlled, such as being responsive to a nutrient in the host cell's medium.

The present invention further provides host cells transformed with a nucleic acid molecule that encodes a protein fragment of the present invention. The host cell can be either prokaryotic or eukaryotic. Eukaryotic cells useful for expression of a protein of the invention are not limited, so long as the cell line is compatible with cell culture methods and compatible with the propagation of the expression vector and expression of the gene product. Preferred eukaryotic host cells include, but are not limited to, yeast, insect and mammalian cells, preferably vertebrate cells such as those from a mouse, rat, monkey or human cell line. Preferred eukaryotic host cells include Chinese hamster ovary (CHO) cells available from the ATCC as CCL61, NIH Swiss mouse embryo cells NIH-3T3 available from the ATCC as CRL1658, baby hamster kidney cells (BHK), and the like eukaryotic tissue culture cell lines.

Transformed host cells of the invention may be cultured under conditions that allow the production of the recombinant protein. Optionally the recombinant protein is isolated from the medium or from the cells; recovery and purification of the protein may not be necessary in some instances where some impurities may be tolerated.

Kits may also be prepared with any of the above described nucleic acid molecules, protein fragments, vector and/or host cells optionally packaged with the reagents needed for a specific assay, such as those described above. In such kits, the protein fragments or other reagents may be attached to a solid support, such as glass or plastic beads.

G. Integrated Procedures Which Utilize the Present Invention

Molecular modeling is provided by the present invention for rational drug design (RDD) of mimetics and ligands of HDM2. As described above, the drug design paradigm uses computer modeling programs to determine potential mimetics and ligands which are expected to interact with sites on the protein. The potential mimetics or ligands are then screened for activity and/or binding and/or interaction. For HDM2-related mimetics or ligands, screening methods can be selected from assays for at least one biological activity of HDM2, e.g. such as blocking p53 binding, according to known method steps. See, for example, Kussie et al., Science 274:948-953 (1996); Bottger et al., J. Mol. Biol. 269:744-756 (1997).

Thus, the tools and methodologies provided by the present invention may be used in procedures for identifying and designing ligands which bind in desirable ways with the target. Such procedures utilize an iterative process whereby ligands are synthesized, tested and characterized. New ligands can be designed based on the information gained in the testing and characterization of the initial ligands and then such newly identified ligands can themselves be tested and characterized. This series of processes may be repeated as many times as necessary to obtain ligands with the desirable binding properties.

The following steps serve as an example of the overall procedure:

1. A biological activity of a target is selected (e.g., binding to p53).

2. A ligand is identified that appears to be in some way associated with the chosen biological activity (e.g., the ligand may be an inhibitor of a known activity). The activity of the ligand may be tested by in vivo and/or in vitro methods.

A ligand of the present invention can be, but is not limited to, at least one selected from a lipid, a nucleic acid, a compound, a protein, an element, an antibody, a saccharide, an isotope, a carbohydrate, an imaging agent, a lipoprotein, a glycoprotein, an enzyme, a detectable probe, and antibody or fragment thereof, or any combination thereof, which can be detectably labeled as for labeling antibodies. Such labels include, but are not limited to, enzymatic labels, radioisotope or radioactive compounds or elements, fluorescent compounds or metals, chemiluminescent compounds and bioluminescent compounds. Alternatively, any other known diagnostic or therapeutic agent can be used in a method of the invention. Suitable compounds are then tested for activities in relationship to the target.

Complexes between HDM2 and ligands are made either by co-crystallization or more commonly by diffusing the small molecule ligand into the crystal. X-ray diffraction data from the complex crystal are measured and a difference electron density map is calculated. This process provides the precise location of the bound ligand on the target molecule. The difference Fourier is calculated using measure diffraction amplitudes and the phases of these reflections calculated from the coordinates.

3. Using the methods of the present invention, X-ray crystallography is utilized to create electron density maps and/or molecular models of the interaction of the ligand with the target molecule.

The entry of the coordinates of the target into the computer programs discussed above results in the calculation of most probable structure of the macromolecule. These structures are combined and refined by additional calculations using such programs to determine the probable or actual three-dimensional structure of the target including potential or actual active or binding sites of ligands. Such molecular modeling (and related) programs useful for rational drug design of ligands or mimetics, are also provided by the present invention.

4. The electron density maps and/or molecular models obtained in Step 3 are compared to the electron density maps and/or molecular models of a non-ligand containing target and the observed/calculated differences are used to specifically locate the binding of the ligand on the target or subunit.

5. Modeling tools, such as computational chemistry and computer modeling, are used to adjust or modify the structure of the ligand so that it can make additional or different interactions with the target.

The ligand design uses computer modeling programs which calculate how different molecules interact with the various sites of a target. This procedure determines potential ligands or mimetics of the ligand(s).

The ligand design uses computer modeling programs which calculate how different molecules interact with the various sites of the target, subunit, or a fragment thereof. Thus, this procedure determines potential ligands or ligand mimetics.

6. The newly designed ligand from Step 5 can be tested for its biological activity using appropriate in vivo or in vitro tests, including the high throughput screening methods discussed above.

The potential ligands or mimetics are then screened for activity relating to HDM2, or at least a fragment thereof. Such screening methods are selected from assays for at least one biological activity of the native target.

The resulting ligands or mimetics, provided by methods of the present invention, are useful for treating, screening or preventing diseases in animals, such as mammals (including humans) and birds.

7. Of course, each of the above steps can be modified as desired by those of skill in the art so as to refine the procedure for the particular goal in mind. Also, additional X-ray diffraction data may be collected on HDM2, HDM2/ligand complexes, HDM2 structural target motifs and HDM2 subunit/ligand complexes at any step or phase of the procedure. Such additional diffraction data can be used to reconstruct electron density maps and molecular models which may further assist in the design and selection of ligands with the desirable binding attributes.

It is to be understood that the present invention is considered to include stereoisomers as well as optical isomers, e.g., mixtures of enantiomers as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in selected compounds, ligands or mimetics of the present series.

Some of the compounds or agents disclosed or discovered by the methods herein may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present invention is also meant to encompass all such possible forms as well as their racemic and resolved forms and mixtures thereof. When the compounds described or discovered herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended to include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

As used herein, the term “chiral center” refers to a carbon atom to which four different groups are attached.

As used herein, the term “enantiomer” or “enantiomeric” refers to a molecule that is nonsuperimposable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.

As used herein, the term “racemic” refers to a mixture of equal parts of enantiomers and which is optically active.

As used herein, the term “resolution” refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule. In the context of this application. the term “resolution” also refers to the amount of detail which can be resolved by the diffraction experiment. Or in other terms, since the inherent disorder of a protein crystal diffraction pattern fades away at some diffraction angle θmax, the corresponding distance d_(min) of the reciprocal lattices is determined by Bragg's law.

$d_{\min} = \frac{\lambda}{2\; \sin \; \theta_{\max}}$

In practice in protein crystallography it is usual to quote the nominal resolution of a protein electron density in terms of d_(min), the minimum lattice distance to which data is included in the calculation of the map.

The compounds of the present invention are also useful at inhibiting the interaction between p53 and MDMX. MDMX, also known as MDM4, is a cellular protein involved in the regulation of the cell cycle. For example, see Riemenschneider et al., Cancer Res. 59(24):6091-6096 (1999).

Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples therefore, specifically point out preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

EXAMPLES Example 1 GST HDM2 Fusion Protein Construction and Expression

cDNA encoding residues 17-125 of HDM2 were cloned and expressed as follows: PCR was performed using ATCC item number 384988 containing partial human MDM2 sequence as template and the following primers:

Forward: 5′-CTCTCTCGGATCCCAGATTCCAGCTTCGGAACAAGAG Reverse: 5′-TATATATCTCGAGTCAGTTCTCACTCACAGATGTACCTGAG.

The PCR product was then digested with BamHI and Xho1 (sequence recognition sites underlined in primers), gel purified, and ligated into pGEX4t-3 which had also been digested with BamHI and XhoI. The purified plasmid was transformed into E. coli strain BL21. Protein was produced at 37° C. in 2 L shake flasks containing 800 ml LB (Laura Bertani medium)+100 μg/ml ampicillin and supplemented with 0.2% glycerol. Briefly media was inoculated with 16 ml of overnight culture and induced with 1 mM IPTG when the absorbance at 600 reached 0.6-0.8 OD. Cells were harvested 5 hr post induction.

For HDM2 23-114, the primers used were as follows:

5′-CGACGATTGGATCCGAACAAAGACCCTG 3′-GGCTACTACTCCGAGTCATTCCTGCTGATTGACTAC

For HDM2 17-111, the primers used were

5′-CTCTCTCGGATCCCAGATTCAGCTTCCGGAACAAGAG 3′-TTCAGCAGCTCGAGTCAATTGACTACTACCAAGTTC

The PCR fragments were cloned and expressed as above with a few exceptions. E. coli strain BL21 RIL was used for expression. Cells were grown at 37° C. until A₆₀₀ of 0.2, then transferred to room temperature and induced at A₆₀₀ of 0.6-0.8 with 0.1 mM IPTG. Cells were harvested 5 hours post induction, centrifuged, and resuspended in PBS to 10 ml/g cell paste.

Protein Production

Cells were lysed in an Avestin microfluidizer, centrifuged, and the supernatant bound to a glutathione sepharose 4B resin (Pharmacia). The resin was washed with PBS and the HDM2 construct of interest was cleaved from the GST-resin by the addition of 2 μg/ml thrombin (Enzyme Research Labs). The cleaved HDM2 was loaded onto a Sepharose SP Fast Flow resin (Pharmacia), and eluted with a 20 mM HEPES pH. 7.5, 150 mM NaCl. Glutathione was added to 5 mM, and the protein stored at −70° C. The resulting protein has an N-terminal Glycine before amino acid 17 (Serine).

Protein Preparation for Crystallography

HDM2 17-111 was complexed with the compound of interest by dialysis at a concentration of 0.7 mg/ml, the buffer brought to 20 mM HEPES pH. 7.4, 100 mM NaCl, 5 mM DTT, filtered through a 0.02 μm filter, and concentrated to 10 mg/ml.

Example 2 Crystallization and Data Collection

In a typical crystallization experiment, 1-2 μl of HDM2 protein, complexed with a compound and concentrated to ca. 10 mg/ml, was mixed in a 1:1 ratio with well solution (1.8-2.4M (NH₄)₂SO₄, 100 mM buffer pH. 6.5-9.0, 2% PEG 400, 100 mM NaSCN) and placed on a glass cover slip. The cover slip was inverted and sealed over a reservoir of 500-1000 μl of well solution and incubated at 4° C. Crystals usually appeared over night and were ready to harvest after 3-7 days. Crystals were harvested with a nylon loop, placed for less than 30 seconds in cryo-solution (2.2M (NH₄)₂SO₄, 100 mM bis-tris-propane pH. 7.5, 2% PEG 400, 100 mM NaSCN, 15% glycerol) and frozen by immersion in liquid nitrogen or liquid propane. Data were collected at 120K on a Bruker AXS M06XCE rotating anode and a SMART 6000 CCD detector. The diffraction data was processed with the Proteum suite (Bruker AXS).

Example 3 Assay Methods Peptide Binding Assay

The inhibition of MDM2 binding to p53 was measured using a p53 peptide analog binding to MDM2 residues 17-125. The published crystal structure of this complex (Kussie, P. H., et al., Science 274:948-953 (1996)) validates this fragment as containing the p53 binding site, and we have solved the X-ray structure of the p53 peptide analog MPRFMDYWEGLN, described to be a peptide inhibitor of the MDM2 p53 interaction (Bottger, A., et al., J Mol Biol 269:744-756 (1997)). The assay uses N terminal fluorescein RFMDYWEGL peptide (F1 9mer). Compound was incubated for 15 minutes with 30 nM fluorescein peptide F1 9mer and 120 nM HDM2 17-125 in 50 mM HEPES pH. 7.5, 150 mM NaCl, 3 mM octyl glucoside. The polarization of the fluorescein label was measured by excitation at 485 nm and emission at 530 nm. Polarization was expressed as a percent of a no compound control, using no MDM2 with F1 9mer as background.

Example 4 HDM2 Atomic Coordinates Table 1 (Compound 1)

Table 1 describes the 3-dimensional atomic coordinates of HDM2 complexed with compound 1 (338437) ((4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid and bound waters in standard pdb-format. The relevant crystallographic data are contained in the REMARK section of Table 1. Two molecules of HDM2, related by non-crystallographic symmetry, are present in the asymmetric unit and are identified by the CHAINID of A for the first molecule and B for the second molecule. The compound (compound 1) is present under the residue name DCB. Compound 1 and HDM2 molecule sharing the same CHAINID are forming a complex.

Example 5 HDM2 Atomic Coordinates Table 2 (Compound 2)

Compound 2 [8-Chloro-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid (876273) and HDM2 protein were cocrystallized as described above in Example 2. Table 2 describes the 3-dimensional atomic coordinates of HDM2 complexed with compound 2 (876273) ([8-Chloro-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid). The relevant crystallographic data are contained in the REMARK section of Table 2. Data were collected as described above. Different crystal forms can be observed under the same crystallization conditions used to obtain the trigonal crystal form.

Example 6 HDM2 Atomic Coordinates Table 3

Table 3 describes the 3-dimensional atomic coordinates of HDM2 cocrystallized with compound 2 (compound 876273: [8-Chloro-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid) in tetragonal spacegroup aligned to the structure of HDM2 complexed with compound 1 (compound 338437 ((4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid). The relevant crystallographic data are contained in the REMARK section of Table 3. Data were collected as described above.

The pdb-format is described on various sites on the web. Depending on the program crystallographic application minor modifications to this format may be found. A good primer is provided by this link at CCP4 “www.ccp4.ac.uk/html/pdbformat.html”. A more extended description can be found at the RCSB home page.

Example 7 Phasing Model Building and Refinement

Phases were obtained by molecular replacement using the published HDM2-structure as a search model in CNX (Brunger, A. T., et al., P.D. Acta Cryst D54:905-921 (1998); Accelrys Inc.). Alternating cycles of structure refinement and model building were carried out according to standard protocols using CNX and O (Jones, T. A., et al., Acta Cryst A47: 110-119 (1991)).

Example 8 Structural Features of HDM2

FIG. 1. Ribbon representation of HDM2 bound to compound 1 (compound 338437: ((4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid).

FIG. 2. Fit of compound 1 (compound 338437: ((4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid into the active site of HDM2 presented as a molecular surface.

Although the present invention has been described in detail with reference to examples above, it is understood that various modifications can be made without departing from the spirit of the invention. All cited patents, patent applications and publications and other documents cited in this application are herein incorporated by reference in their entirety.

TABLE 1 compound 338437 ((4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7- iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid REMARK coordinates from restrained individual B-factor refinement REMARK refinement resolution: 500.0-2.6 A REMARK starting r = 0.2398 free_r = 0.2763 REMARK final r = 0.2390 free_r = 0.2765 REMARK B rmsd for bonded mainchain atoms = 1.358 target = 1.5 REMARK B rmsd for bonded sidechain atoms = 1.887 target = 2.0 REMARK B rmsd for angle mainchain atoms = 2.371 target = 2.0 REMARK B rmsd for angle sidechain atoms = 2.965 target = 2.5 REMARK rweight = 0.1000 (with wa = 2.71183) REMARK target = mlf steps = 30 REMARK sg = P3(2)21 a = 98.486 b = 98.486 c = 74.038 alpha = 90 beta = 90 gamma = 120 REMARK parameter file 1 : MSI_CNX_TOPPAR:protein_rep.param REMARK parameter file 2 : dcb.par REMARK parameter file 3 : MSI_CNX_TOPPAR:water_rep.param REMARK molecular structure file: cycle8.psf REMARK input coordinates: minimize.pdb REMARK reflection file = ../M338437_P3221.cv REMARK ncs = none REMARK B-correction resolution: 6.0-2.6 REMARK initial B-factor correction applied to fobs: REMARK B11 = 5.509 B22 = 5.509 B33 = −11.019 REMARK B12 = 0.263 B13 = 0.000 B23 = 0.000 REMARK B-factor correction applied to coordinate array B:  0.036 REMARK bulk solvent: (Mask) density level = 0.372649 e/A{circumflex over ( )}3, B-factor = 25.2844 A{circumflex over ( )}2 REMARK reflections with |Fobs|/sigma_F <0.0 rejected REMARK reflections with |Fobs| >10000 * rms(Fobs) rejected REMARK theoretical total number of refl. in resol. range: 13090 (100.0%) REMARK number of unobserved reflections (no entry or |F| = 0): 176 (1.3%) REMARK number of reflections rejected: 0 (0.0%) REMARK total number of reflections used: 12914 (98.7%) REMARK number of reflections in working set: 11964 (91.4%) REMARK number of reflections in test set: 950 (7.3%) CRYST1  98.486  98.486  74.038  90.00  90.00  120.00 P 32 2 1 REMARK FILENAME = “bindividual.pdb” REMARK Written by CNX VERSION: 2000.12 ATOM 1 C GLY A 16 47.235 17.293 23.953 1.00 68.07 A C ATOM 2 O GLY A 16 48.284 16.646 23.907 1.00 68.13 A O ATOM 3 N GLY A 16 44.698 17.056 23.726 1.00 66.75 A N ATOM 4 CA GLY A 16 46.042 16.904 23.083 1.00 67.77 A C ATOM 5 N SER A 17 47.083 18.352 24.744 1.00 67.81 A N ATOM 6 CA SER A 17 48.154 18.831 25.618 1.00 66.82 A C ATOM 7 CB SER A 17 48.407 17.831 26.743 1.00 67.50 A C ATOM 8 OG SER A 17 47.247 17.658 27.540 1.00 67.94 A O ATOM 9 C SER A 17 49.456 19.118 24.864 1.00 65.58 A C ATOM 10 O SER A 17 49.699 20.265 24.476 1.00 66.26 A O ATOM 11 N GLN A 18 50.304 18.108 24.657 1.00 63.21 A N ATOM 12 CA GLN A 18 51.543 18.367 23.921 1.00 60.51 A C ATOM 13 CB GLN A 18 52.778 17.995 24.735 1.00 60.31 A C ATOM 14 CG GLN A 18 53.833 19.070 24.574 1.00 59.93 A C ATOM 15 CD GLN A 18 53.200 20.457 24.506 1.00 59.70 A C ATOM 16 OE1 GLN A 18 52.584 20.919 25.464 1.00 59.78 A O ATOM 17 NE2 GLN A 18 53.333 21.112 23.362 1.00 59.29 A N ATOM 18 C GLN A 18 51.619 17.752 22.529 1.00 58.18 A C ATOM 19 O GLN A 18 52.569 17.049 22.158 1.00 57.08 A O ATOM 20 N ILE A 19 50.573 18.064 21.776 1.00 54.61 A N ATOM 21 CA ILE A 19 50.380 17.673 20.399 1.00 49.59 A C ATOM 22 CB ILE A 19 49.130 16.771 20.256 1.00 47.27 A C ATOM 23 CG2 ILE A 19 48.730 16.643 18.802 1.00 46.21 A C ATOM 24 CG1 ILE A 19 49.407 15.403 20.880 1.00 44.27 A C ATOM 25 CD1 ILE A 19 50.565 14.675 20.263 1.00 40.62 A C ATOM 26 C ILE A 19 50.112 19.056 19.806 1.00 48.49 A C ATOM 27 O ILE A 19 49.344 19.838 20.374 1.00 46.95 A O ATOM 28 N PRO A 20 50.765 19.396 18.686 1.00 47.71 A N ATOM 29 CD PRO A 20 51.681 18.610 17.840 1.00 46.47 A C ATOM 30 CA PRO A 20 50.521 20.721 18.107 1.00 46.58 A C ATOM 31 CB PRO A 20 51.072 20.574 16.695 1.00 46.92 A C ATOM 32 CG PRO A 20 52.256 19.667 16.919 1.00 46.74 A C ATOM 33 C PRO A 20 49.041 21.112 18.134 1.00 45.69 A C ATOM 34 O PRO A 20 48.181 20.376 17.636 1.00 45.19 A O ATOM 35 N ALA A 21 48.751 22.264 18.738 1.00 43.36 A N ATOM 36 CA ALA A 21 47.379 22.755 18.832 1.00 40.68 A C ATOM 37 CB ALA A 21 47.371 24.193 19.350 1.00 39.15 A C ATOM 38 C ALA A 21 46.710 22.676 17.460 1.00 39.20 A C ATOM 39 O ALA A 21 45.518 22.379 17.351 1.00 38.64 A O ATOM 40 N SER A 22 47.490 22.937 16.414 1.00 37.13 A N ATOM 41 CA SER A 22 46.996 22.881 15.042 1.00 34.91 A C ATOM 42 CB SER A 22 48.140 23.167 14.077 1.00 36.91 A C ATOM 43 OG SER A 22 49.177 22.202 14.208 1.00 39.98 A O ATOM 44 C SER A 22 46.428 21.494 14.755 1.00 32.16 A C ATOM 45 O SER A 22 45.349 21.356 14.179 1.00 32.41 A O ATOM 46 N GLU A 23 47.179 20.474 15.159 1.00 28.39 A N ATOM 47 CA GLU A 23 46.785 19.084 14.981 1.00 25.53 A C ATOM 48 CB GLU A 23 47.986 18.167 15.280 1.00 24.74 A C ATOM 49 CG GLU A 23 47.650 16.698 15.507 1.00 22.09 A C ATOM 50 CD GLU A 23 48.881 15.805 15.524 1.00 21.23 A C ATOM 51 OE1 GLU A 23 49.956 16.270 15.952 1.00 22.29 A O ATOM 52 OE2 GLU A 23 48.775 14.631 15.120 1.00 19.31 A O ATOM 53 C GLU A 23 45.597 18.733 15.879 1.00 23.76 A C ATOM 54 O GLU A 23 44.756 17.928 15.501 1.00 21.78 A O ATOM 55 N GLN A 24 45.524 19.345 17.059 1.00 22.33 A N ATOM 56 CA GLN A 24 44.423 19.086 17.985 1.00 21.86 A C ATOM 57 CB GLN A 24 44.628 19.838 19.294 1.00 22.56 A C ATOM 58 CG GLN A 24 45.721 19.267 20.157 1.00 26.35 A C ATOM 59 CD GLN A 24 45.896 20.017 21.458 1.00 27.27 A C ATOM 60 OE1 GLN A 24 44.964 20.131 22.262 1.00 27.74 A O ATOM 61 NE2 GLN A 24 47.101 20.533 21.676 1.00 29.00 A N ATOM 62 C GLN A 24 43.063 19.464 17.423 1.00 21.99 A C ATOM 63 O GLN A 24 42.047 18.871 17.786 1.00 21.50 A O ATOM 64 N GLU A 25 43.045 20.456 16.542 1.00 22.95 A N ATOM 65 CA GLU A 25 41.800 20.921 15.939 1.00 24.26 A C ATOM 66 CB GLU A 25 41.874 22.432 15.665 1.00 25.71 A C ATOM 67 CG GLU A 25 42.226 23.265 16.884 1.00 27.74 A C ATOM 68 CD GLU A 25 41.218 23.107 18.006 1.00 30.63 A C ATOM 69 OE1 GLU A 25 41.640 23.112 19.187 1.00 32.01 A O ATOM 70 OE2 GLU A 25 40.005 22.987 17.705 1.00 30.20 A O ATOM 71 C GLU A 25 41.479 20.179 14.644 1.00 23.62 A C ATOM 72 O GLU A 25 40.472 20.461 13.995 1.00 24.16 A O ATOM 73 N THR A 26 42.337 19.237 14.267 1.00 22.53 A N ATOM 74 CA THR A 26 42.123 18.462 13.052 1.00 21.97 A C ATOM 75 CB THR A 26 43.138 17.299 12.955 1.00 23.07 A C ATOM 76 OG1 THR A 26 44.472 17.828 12.972 1.00 22.96 A O ATOM 77 CG2 THR A 26 42.920 16.499 11.675 1.00 21.12 A C ATOM 78 C THR A 26 40.705 17.894 13.031 1.00 21.66 A C ATOM 79 O THR A 26 40.281 17.217 13.962 1.00 19.94 A O ATOM 80 N LEU A 27 39.974 18.187 11.963 1.00 23.11 A N ATOM 81 CA LEU A 27 38.602 17.713 11.805 1.00 25.25 A C ATOM 82 CB LEU A 27 37.888 18.593 10.775 1.00 26.19 A C ATOM 83 CG LEU A 27 36.362 18.646 10.828 1.00 28.80 A C ATOM 84 CD1 LEU A 27 35.918 19.212 12.183 1.00 26.94 A C ATOM 85 CD2 LEU A 27 35.840 19.512 9.677 1.00 28.47 A C ATOM 86 C LEU A 27 38.620 16.240 11.350 1.00 24.95 A C ATOM 87 O LEU A 27 39.275 15.901 10.359 1.00 26.23 A O ATOM 88 N VAL A 28 37.898 15.373 12.064 1.00 22.99 A N ATOM 89 CA VAL A 28 37.882 13.938 11.749 1.00 20.72 A C ATOM 90 CB VAL A 28 38.810 13.143 12.719 1.00 18.95 A C ATOM 91 CG1 VAL A 28 40.213 13.729 12.734 1.00 17.23 A C ATOM 92 CG2 VAL A 28 38.230 13.164 14.118 1.00 16.75 A C ATOM 93 C VAL A 28 36.500 13.284 11.833 1.00 21.21 A C ATOM 94 O VAL A 28 35.593 13.805 12.486 1.00 19.81 A O ATOM 95 N ARG A 29 36.365 12.131 11.174 1.00 22.25 A N ATOM 96 CA ARG A 29 35.126 11.340 11.159 1.00 23.75 A C ATOM 97 CB ARG A 29 34.559 11.229 9.742 1.00 25.97 A C ATOM 98 CG ARG A 29 33.678 12.388 9.308 1.00 32.69 A C ATOM 99 CD ARG A 29 33.206 12.199 7.866 1.00 38.68 A C ATOM 100 NE ARG A 29 32.256 13.231 7.455 1.00 45.71 A N ATOM 101 CZ ARG A 29 31.002 13.322 7.901 1.00 50.53 A C ATOM 102 NH1 ARG A 29 30.534 12.439 8.777 1.00 52.47 A N ATOM 103 NH2 ARG A 29 30.208 14.299 7.472 1.00 52.60 A N ATOM 104 C ARG A 29 35.402 9.931 11.680 1.00 22.61 A C ATOM 105 O ARG A 29 35.891 9.076 10.944 1.00 23.74 A O ATOM 106 N PRO A 30 35.094 9.669 12.959 1.00 20.77 A N ATOM 107 CD PRO A 30 34.654 10.607 14.006 1.00 19.85 A C ATOM 108 CA PRO A 30 35.334 8.340 13.523 1.00 19.49 A C ATOM 109 CB PRO A 30 34.798 8.471 14.951 1.00 18.27 A C ATOM 110 CG PRO A 30 35.081 9.895 15.276 1.00 18.94 A C ATOM 111 C PRO A 30 34.655 7.206 12.757 1.00 19.01 A C ATOM 112 O PRO A 30 33.552 7.367 12.236 1.00 18.19 A O ATOM 113 N LYS A 31 35.332 6.063 12.689 1.00 19.05 A N ATOM 114 CA LYS A 31 34.790 4.880 12.033 1.00 19.18 A C ATOM 115 CB LYS A 31 35.919 3.891 11.703 1.00 18.74 A C ATOM 116 CG LYS A 31 36.881 4.392 10.630 1.00 18.49 A C ATOM 117 CD LYS A 31 38.048 3.442 10.409 1.00 16.87 A C ATOM 118 CE LYS A 31 39.007 3.982 9.359 1.00 16.16 A C ATOM 119 NZ LYS A 31 40.238 3.161 9.254 1.00 17.03 A N ATOM 120 C LYS A 31 33.777 4.260 13.009 1.00 19.76 A C ATOM 121 O LYS A 31 33.862 4.465 14.221 1.00 19.24 A O ATOM 122 N PRO A 32 32.816 3.480 12.492 1.00 20.78 A N ATOM 123 CD PRO A 32 32.772 2.971 11.106 1.00 20.08 A C ATOM 124 CA PRO A 32 31.778 2.840 13.311 1.00 20.65 A C ATOM 125 CB PRO A 32 31.376 1.640 12.465 1.00 18.59 A C ATOM 126 CG PRO A 32 31.460 2.197 11.079 1.00 19.84 A C ATOM 127 C PRO A 32 32.108 2.460 14.761 1.00 21.61 A C ATOM 128 O PRO A 32 31.412 2.877 15.695 1.00 20.03 A O ATOM 129 N LEU A 33 33.164 1.679 14.955 1.00 22.55 A N ATOM 130 CA LEU A 33 33.522 1.237 16.296 1.00 23.06 A C ATOM 131 CB LEU A 33 34.677 0.236 16.223 1.00 23.79 A C ATOM 132 CG LEU A 33 34.537 −0.992 17.135 1.00 24.29 A C ATOM 133 CD1 LEU A 33 33.136 −1.597 17.020 1.00 22.52 A C ATOM 134 CD2 LEU A 33 35.597 −2.015 16.747 1.00 23.61 A C ATOM 135 C LEU A 33 33.850 2.370 17.260 1.00 23.64 A C ATOM 136 O LEU A 33 33.348 2.385 18.382 1.00 25.22 A O ATOM 137 N LEU A 34 34.684 3.319 16.838 1.00 23.73 A N ATOM 138 CA LEU A 34 35.033 4.445 17.707 1.00 23.80 A C ATOM 139 CB LEU A 34 36.173 5.281 17.108 1.00 22.45 A C ATOM 140 CG LEU A 34 36.459 6.603 17.842 1.00 21.72 A C ATOM 141 CD1 LEU A 34 36.722 6.324 19.310 1.00 20.49 A C ATOM 142 CD2 LEU A 34 37.647 7.324 17.209 1.00 20.12 A C ATOM 143 C LEU A 34 33.829 5.351 17.949 1.00 24.92 A C ATOM 144 O LEU A 34 33.641 5.867 19.058 1.00 25.03 A O ATOM 145 N LEU A 35 33.019 5.549 16.911 1.00 24.02 A N ATOM 146 CA LEU A 35 31.841 6.394 17.027 1.00 24.15 A C ATOM 147 CB LEU A 35 31.113 6.470 15.690 1.00 21.76 A C ATOM 148 CG LEU A 35 30.415 7.787 15.341 1.00 20.69 A C ATOM 149 CD1 LEU A 35 29.176 7.489 14.522 1.00 17.66 A C ATOM 150 CD2 LEU A 35 30.026 8.526 16.589 1.00 20.82 A C ATOM 151 C LEU A 35 30.889 5.849 18.101 1.00 26.94 A C ATOM 152 O LEU A 35 30.302 6.617 18.870 1.00 27.88 A O ATOM 153 N LYS A 36 30.735 4.527 18.152 1.00 27.77 A N ATOM 154 CA LYS A 36 29.859 3.913 19.140 1.00 28.78 A C ATOM 155 CB LYS A 36 29.778 2.398 18.939 1.00 31.12 A C ATOM 156 CG LYS A 36 29.062 1.687 20.081 1.00 35.08 A C ATOM 157 CD LYS A 36 29.472 0.220 20.223 1.00 38.33 A C ATOM 158 CE LYS A 36 28.711 −0.681 19.268 1.00 41.52 A C ATOM 159 NZ LYS A 36 29.044 −2.120 19.487 1.00 43.62 A N ATOM 160 C LYS A 36 30.397 4.200 20.530 1.00 28.98 A C ATOM 161 O LYS A 36 29.632 4.463 21.459 1.00 29.52 A O ATOM 162 N LEU A 37 31.719 4.137 20.664 1.00 28.82 A N ATOM 163 CA LEU A 37 32.396 4.395 21.936 1.00 28.09 A C ATOM 164 CB LEU A 37 33.908 4.244 21.751 1.00 28.11 A C ATOM 165 CG LEU A 37 34.888 4.330 22.929 1.00 27.55 A C ATOM 166 CD1 LEU A 37 34.655 5.592 23.736 1.00 27.78 A C ATOM 167 CD2 LEU A 37 34.730 3.109 23.788 1.00 27.77 A C ATOM 168 C LEU A 37 32.079 5.814 22.402 1.00 28.36 A C ATOM 169 O LEU A 37 31.730 6.034 23.559 1.00 27.57 A O ATOM 170 N LEU A 38 32.209 6.772 21.486 1.00 28.83 A N ATOM 171 CA LEU A 38 31.951 8.175 21.785 1.00 27.42 A C ATOM 172 CB LEU A 38 32.324 9.045 20.581 1.00 25.41 A C ATOM 173 CG LEU A 38 33.787 8.973 20.141 1.00 25.18 A C ATOM 174 CD1 LEU A 38 34.015 9.980 19.042 1.00 24.55 A C ATOM 175 CD2 LEU A 38 34.715 9.251 21.315 1.00 25.40 A C ATOM 176 C LEU A 38 30.504 8.449 22.186 1.00 27.27 A C ATOM 177 O LEU A 38 30.239 8.989 23.259 1.00 27.56 A O ATOM 178 N LYS A 39 29.562 8.083 21.327 1.00 26.08 A N ATOM 179 CA LYS A 39 28.163 8.325 21.638 1.00 24.78 A C ATOM 180 CB LYS A 39 27.294 7.885 20.461 1.00 23.77 A C ATOM 181 CG LYS A 39 27.593 8.696 19.215 1.00 25.97 A C ATOM 182 CD LYS A 39 26.657 8.409 18.051 1.00 26.72 A C ATOM 183 CE LYS A 39 26.943 9.401 16.916 1.00 29.24 A C ATOM 184 NZ LYS A 39 26.169 9.183 15.657 1.00 31.08 A N ATOM 185 C LYS A 39 27.708 7.655 22.940 1.00 23.69 A C ATOM 186 O LYS A 39 26.812 8.156 23.623 1.00 24.40 A O ATOM 187 N SER A 40 28.338 6.545 23.305 1.00 21.60 A N ATOM 188 CA SER A 40 27.946 5.850 24.522 1.00 18.78 A C ATOM 189 CB SER A 40 28.602 4.465 24.593 1.00 16.27 A C ATOM 190 OG SER A 40 29.947 4.538 25.020 1.00 13.26 A O ATOM 191 C SER A 40 28.299 6.663 25.766 1.00 18.97 A C ATOM 192 O SER A 40 27.808 6.376 26.854 1.00 18.43 A O ATOM 193 N VAL A 41 29.157 7.667 25.616 1.00 18.55 A N ATOM 194 CA VAL A 41 29.515 8.496 26.758 1.00 19.39 A C ATOM 195 CB VAL A 41 31.057 8.645 26.940 1.00 20.54 A C ATOM 196 CG1 VAL A 41 31.630 7.402 27.607 1.00 18.57 A C ATOM 197 CG2 VAL A 41 31.733 8.891 25.600 1.00 21.46 A C ATOM 198 C VAL A 41 28.887 9.881 26.662 1.00 20.20 A C ATOM 199 O VAL A 41 29.218 10.771 27.444 1.00 19.90 A O ATOM 200 N GLY A 42 27.975 10.062 25.707 1.00 20.98 A N ATOM 201 CA GLY A 42 27.306 11.345 25.571 1.00 21.00 A C ATOM 202 C GLY A 42 27.542 12.155 24.309 1.00 22.06 A C ATOM 203 O GLY A 42 26.809 13.107 24.060 1.00 23.06 A O ATOM 204 N ALA A 43 28.557 11.807 23.522 1.00 23.02 A N ATOM 205 CA ALA A 43 28.841 12.530 22.280 1.00 23.42 A C ATOM 206 CB ALA A 43 30.075 11.940 21.593 1.00 20.28 A C ATOM 207 C ALA A 43 27.632 12.427 21.354 1.00 23.40 A C ATOM 208 O ALA A 43 26.816 11.517 21.495 1.00 21.98 A O ATOM 209 N GLN A 44 27.505 13.352 20.407 1.00 25.42 A N ATOM 210 CA GLN A 44 26.369 13.279 19.502 1.00 27.06 A C ATOM 211 CB GLN A 44 25.130 13.872 20.165 1.00 27.82 A C ATOM 212 CG GLN A 44 25.315 15.232 20.763 1.00 28.96 A C ATOM 213 CD GLN A 44 24.576 15.357 22.085 1.00 32.56 A C ATOM 214 OE1 GLN A 44 24.357 16.462 22.585 1.00 34.47 A O ATOM 215 NE2 GLN A 44 24.200 14.215 22.668 1.00 31.28 A N ATOM 216 C GLN A 44 26.520 13.854 18.106 1.00 26.84 A C ATOM 217 O GLN A 44 25.532 14.268 17.500 1.00 26.83 A O ATOM 218 N LYS A 45 27.745 13.881 17.592 1.00 25.93 A N ATOM 219 CA LYS A 45 27.980 14.363 16.230 1.00 25.65 A C ATOM 220 CB LYS A 45 28.960 15.544 16.198 1.00 25.47 A C ATOM 221 CG LYS A 45 28.546 16.767 16.992 1.00 24.64 A C ATOM 222 CD LYS A 45 29.614 17.860 16.948 1.00 21.21 A C ATOM 223 CE LYS A 45 30.907 17.410 17.615 1.00 19.16 A C ATOM 224 NZ LYS A 45 31.849 18.543 17.785 1.00 16.01 A N ATOM 225 C LYS A 45 28.627 13.199 15.508 1.00 24.50 A C ATOM 226 O LYS A 45 28.904 12.162 16.112 1.00 24.58 A O ATOM 227 N ASP A 46 28.861 13.359 14.219 1.00 22.87 A N ATOM 228 CA ASP A 46 29.539 12.314 13.483 1.00 23.75 A C ATOM 229 CB ASP A 46 28.765 11.931 12.219 1.00 26.21 A C ATOM 230 CG ASP A 46 27.451 11.222 12.525 1.00 28.44 A C ATOM 231 OD1 ASP A 46 27.379 10.480 13.530 1.00 28.33 A O ATOM 232 OD2 ASP A 46 26.489 11.396 11.746 1.00 30.59 A O ATOM 233 C ASP A 46 30.913 12.872 13.125 1.00 23.42 A C ATOM 234 O ASP A 46 31.820 12.134 12.759 1.00 24.56 A O ATOM 235 N THR A 47 31.062 14.188 13.245 1.00 22.36 A N ATOM 236 CA THR A 47 32.326 14.847 12.939 1.00 20.77 A C ATOM 237 CB THR A 47 32.151 15.896 11.831 1.00 21.07 A C ATOM 238 OG1 THR A 47 31.573 15.276 10.676 1.00 22.41 A O ATOM 239 CG2 THR A 47 33.496 16.498 11.458 1.00 19.56 A C ATOM 240 C THR A 47 32.859 15.536 14.187 1.00 19.61 A C ATOM 241 O THR A 47 32.114 16.213 14.893 1.00 19.20 A O ATOM 242 N TYR A 48 34.147 15.364 14.461 1.00 17.90 A N ATOM 243 CA TYR A 48 34.744 15.966 15.646 1.00 17.29 A C ATOM 244 CB TYR A 48 34.904 14.924 16.763 1.00 17.51 A C ATOM 245 CG TYR A 48 33.645 14.195 17.178 1.00 18.47 A C ATOM 246 CD1 TYR A 48 33.094 13.199 16.376 1.00 17.60 A C ATOM 247 CE1 TYR A 48 31.926 12.549 16.743 1.00 19.18 A C ATOM 248 CD2 TYR A 48 32.993 14.518 18.368 1.00 18.07 A C ATOM 249 CE2 TYR A 48 31.826 13.877 18.746 1.00 18.21 A C ATOM 250 CZ TYR A 48 31.291 12.893 17.930 1.00 19.97 A C ATOM 251 OH TYR A 48 30.112 12.264 18.294 1.00 20.10 A O ATOM 252 C TYR A 48 36.123 16.528 15.356 1.00 17.64 A C ATOM 253 O TYR A 48 36.650 16.401 14.245 1.00 19.08 A O ATOM 254 N THR A 49 36.695 17.172 16.364 1.00 16.11 A N ATOM 255 CA THR A 49 38.057 17.677 16.267 1.00 16.21 A C ATOM 256 CB THR A 49 38.219 19.061 16.891 1.00 15.01 A C ATOM 257 OG1 THR A 49 38.028 18.969 18.309 1.00 14.67 A O ATOM 258 CG2 THR A 49 37.212 20.006 16.316 1.00 14.41 A C ATOM 259 C THR A 49 38.766 16.672 17.164 1.00 16.33 A C ATOM 260 O THR A 49 38.142 16.091 18.057 1.00 16.33 A O ATOM 261 N MET A 50 40.050 16.448 16.937 1.00 16.12 A N ATOM 262 CA MET A 50 40.770 15.500 17.765 1.00 16.31 A C ATOM 263 CB MET A 50 42.253 15.515 17.411 1.00 16.08 A C ATOM 264 CG MET A 50 42.550 14.804 16.100 1.00 15.76 A C ATOM 265 SD MET A 50 42.007 13.088 16.174 1.00 15.40 A S ATOM 266 CE MET A 50 43.383 12.364 17.108 1.00 12.28 A C ATOM 267 C MET A 50 40.570 15.820 19.236 1.00 17.20 A C ATOM 268 O MET A 50 40.300 14.931 20.034 1.00 18.81 A O ATOM 269 N LYS A 51 40.679 17.099 19.581 1.00 16.94 A N ATOM 270 CA LYS A 51 40.515 17.551 20.952 1.00 16.59 A C ATOM 271 CB LYS A 51 40.588 19.083 20.993 1.00 19.46 A C ATOM 272 CG LYS A 51 40.773 19.662 22.382 1.00 24.41 A C ATOM 273 CD LYS A 51 41.177 21.132 22.333 1.00 29.49 A C ATOM 274 CE LYS A 51 41.633 21.623 23.711 1.00 30.87 A C ATOM 275 NZ LYS A 51 42.111 23.039 23.693 1.00 32.84 A N ATOM 276 C LYS A 51 39.195 17.059 21.555 1.00 15.64 A C ATOM 277 O LYS A 51 39.133 16.677 22.729 1.00 14.01 A O ATOM 278 N GLU A 52 38.139 17.062 20.750 1.00 15.07 A N ATOM 279 CA GLU A 52 36.837 16.613 21.234 1.00 15.62 A C ATOM 280 CB GLU A 52 35.738 17.017 20.254 1.00 16.29 A C ATOM 281 CG GLU A 52 35.586 18.520 20.127 1.00 18.24 A C ATOM 282 CD GLU A 52 34.649 18.921 19.018 1.00 19.03 A C ATOM 283 OE1 GLU A 52 34.764 18.341 17.918 1.00 22.90 A O ATOM 284 OE2 GLU A 52 33.812 19.821 19.236 1.00 19.46 A O ATOM 285 C GLU A 52 36.808 15.110 21.454 1.00 15.03 A C ATOM 286 O GLU A 52 36.232 14.638 22.435 1.00 16.38 A O ATOM 287 N VAL A 53 37.432 14.361 20.546 1.00 14.02 A N ATOM 288 CA VAL A 53 37.475 12.908 20.661 1.00 12.12 A C ATOM 289 CB VAL A 53 38.216 12.274 19.478 1.00 11.38 A C ATOM 290 CG1 VAL A 53 38.129 10.769 19.566 1.00 10.68 A C ATOM 291 CG2 VAL A 53 37.612 12.750 18.171 1.00 12.22 A C ATOM 292 C VAL A 53 38.191 12.540 21.955 1.00 12.50 A C ATOM 293 O VAL A 53 37.691 11.744 22.761 1.00 12.84 A O ATOM 294 N LEU A 54 39.362 13.129 22.158 1.00 9.57 A N ATOM 295 CA LEU A 54 40.109 12.871 23.365 1.00 10.63 A C ATOM 296 CB LEU A 54 41.365 13.726 23.405 1.00 11.63 A C ATOM 297 CG LEU A 54 42.520 13.131 22.609 1.00 11.73 A C ATOM 298 CD1 LEU A 54 43.563 14.192 22.418 1.00 14.32 A C ATOM 299 CD2 LEU A 54 43.095 11.922 23.344 1.00 12.23 A C ATOM 300 C LEU A 54 39.260 13.159 24.581 1.00 12.08 A C ATOM 301 O LEU A 54 39.280 12.398 25.541 1.00 13.29 A O ATOM 302 N PHE A 55 38.508 14.256 24.545 1.00 13.96 A N ATOM 303 CA PHE A 55 37.653 14.612 25.675 1.00 14.56 A C ATOM 304 CB PHE A 55 36.874 15.901 25.391 1.00 15.14 A C ATOM 305 CG PHE A 55 35.984 16.330 26.530 1.00 12.59 A C ATOM 306 CD1 PHE A 55 36.478 17.135 27.551 1.00 12.50 A C ATOM 307 CD2 PHE A 55 34.674 15.870 26.614 1.00 11.59 A C ATOM 308 CE1 PHE A 55 35.679 17.473 28.643 1.00 12.57 A C ATOM 309 CE2 PHE A 55 33.869 16.198 27.696 1.00 10.75 A C ATOM 310 CZ PHE A 55 34.373 17.001 28.714 1.00 12.37 A C ATOM 311 C PHE A 55 36.654 13.503 25.998 1.00 15.87 A C ATOM 312 O PHE A 55 36.537 13.073 27.149 1.00 14.84 A O ATOM 313 N TYR A 56 35.916 13.059 24.985 1.00 15.22 A N ATOM 314 CA TYR A 56 34.928 12.013 25.201 1.00 16.95 A C ATOM 315 CB TYR A 56 34.070 11.832 23.952 1.00 14.70 A C ATOM 316 CG TYR A 56 33.084 12.953 23.737 1.00 14.95 A C ATOM 317 CD1 TYR A 56 32.015 13.148 24.615 1.00 15.85 A C ATOM 318 CE1 TYR A 56 31.086 14.169 24.406 1.00 17.59 A C ATOM 319 CD2 TYR A 56 33.205 13.810 22.645 1.00 15.37 A C ATOM 320 CE2 TYR A 56 32.290 14.833 22.423 1.00 16.46 A C ATOM 321 CZ TYR A 56 31.231 15.007 23.303 1.00 18.11 A C ATOM 322 OH TYR A 56 30.311 16.001 23.059 1.00 18.28 A O ATOM 323 C TYR A 56 35.598 10.698 25.580 1.00 17.45 A C ATOM 324 O TYR A 56 35.117 9.958 26.440 1.00 16.40 A O ATOM 325 N LEU A 57 36.717 10.411 24.931 1.00 18.36 A N ATOM 326 CA LEU A 57 37.449 9.194 25.217 1.00 17.30 A C ATOM 327 CB LEU A 57 38.621 9.081 24.245 1.00 15.20 A C ATOM 328 CG LEU A 57 38.903 7.706 23.644 1.00 16.42 A C ATOM 329 CD1 LEU A 57 37.637 7.037 23.166 1.00 16.54 A C ATOM 330 CD2 LEU A 57 39.860 7.885 22.499 1.00 18.63 A C ATOM 331 C LEU A 57 37.915 9.332 26.675 1.00 17.78 A C ATOM 332 O LEU A 57 38.074 8.350 27.398 1.00 17.21 A O ATOM 333 N GLY A 58 38.099 10.576 27.103 1.00 17.15 A N ATOM 334 CA GLY A 58 38.515 10.832 28.464 1.00 16.26 A C ATOM 335 C GLY A 58 37.406 10.511 29.438 1.00 17.52 A C ATOM 336 O GLY A 58 37.656 9.909 30.482 1.00 18.49 A O ATOM 337 N GLN A 59 36.179 10.906 29.114 1.00 15.94 A N ATOM 338 CA GLN A 59 35.071 10.617 30.010 1.00 17.18 A C ATOM 339 CB GLN A 59 33.761 11.199 29.481 1.00 17.70 A C ATOM 340 CG GLN A 59 33.713 12.720 29.500 1.00 18.77 A C ATOM 341 CD GLN A 59 34.064 13.281 30.859 1.00 19.30 A C ATOM 342 OE1 GLN A 59 33.435 12.939 31.856 1.00 20.86 A O ATOM 343 NE2 GLN A 59 35.078 14.145 30.909 1.00 18.39 A N ATOM 344 C GLN A 59 34.966 9.115 30.109 1.00 17.93 A C ATOM 345 O GLN A 59 34.903 8.552 31.199 1.00 17.50 A O ATOM 346 N TYR A 60 34.984 8.473 28.949 1.00 19.35 A N ATOM 347 CA TYR A 60 34.906 7.023 28.854 1.00 19.97 A C ATOM 348 CB TYR A 60 35.270 6.580 27.450 1.00 18.67 A C ATOM 349 CG TYR A 60 35.061 5.121 27.258 1.00 18.93 A C ATOM 350 CD1 TYR A 60 33.783 4.608 27.114 1.00 19.95 A C ATOM 351 CE1 TYR A 60 33.573 3.256 26.945 1.00 22.90 A C ATOM 352 CD2 TYR A 60 36.139 4.243 27.235 1.00 21.13 A C ATOM 353 CE2 TYR A 60 35.946 2.880 27.068 1.00 22.87 A C ATOM 354 CZ TYR A 60 34.656 2.393 26.920 1.00 24.39 A C ATOM 355 OH TYR A 60 34.439 1.051 26.722 1.00 26.24 A O ATOM 356 C TYR A 60 35.833 6.309 29.837 1.00 20.15 A C ATOM 357 O TYR A 60 35.384 5.527 30.682 1.00 19.42 A O ATOM 358 N ILE A 61 37.130 6.564 29.701 1.00 20.01 A N ATOM 359 CA ILE A 61 38.116 5.949 30.574 1.00 21.24 A C ATOM 360 CB ILE A 61 39.508 6.556 30.346 1.00 19.34 A C ATOM 361 CG2 ILE A 61 40.449 6.169 31.481 1.00 17.74 A C ATOM 362 CG1 ILE A 61 40.050 6.096 28.993 1.00 18.22 A C ATOM 363 CD1 ILE A 61 41.343 6.774 28.602 1.00 17.99 A C ATOM 364 C ILE A 61 37.717 6.175 32.020 1.00 22.76 A C ATOM 365 O ILE A 61 37.731 5.261 32.837 1.00 19.91 A O ATOM 366 N MET A 62 37.342 7.414 32.309 1.00 26.52 A N ATOM 367 CA MET A 62 36.951 7.827 33.645 1.00 28.53 A C ATOM 368 CB MET A 62 36.735 9.338 33.661 1.00 28.55 A C ATOM 369 CG MET A 62 37.153 9.971 34.948 1.00 29.96 A C ATOM 370 SD MET A 62 38.843 9.527 35.301 1.00 32.30 A S ATOM 371 CE MET A 62 39.644 11.112 35.168 1.00 34.41 A C ATOM 372 C MET A 62 35.709 7.120 34.180 1.00 29.87 A C ATOM 373 O MET A 62 35.689 6.691 35.336 1.00 31.34 A O ATOM 374 N THR A 63 34.677 6.992 33.350 1.00 30.81 A N ATOM 375 CA THR A 63 33.450 6.342 33.792 1.00 31.38 A C ATOM 376 CB THR A 63 32.265 6.625 32.834 1.00 31.49 A C ATOM 377 OG1 THR A 63 31.505 5.427 32.649 1.00 33.06 A O ATOM 378 CG2 THR A 63 32.747 7.120 31.501 1.00 32.85 A C ATOM 379 C THR A 63 33.588 4.836 34.002 1.00 31.82 A C ATOM 380 O THR A 63 33.045 4.301 34.975 1.00 32.68 A O ATOM 381 N LYS A 64 34.305 4.149 33.115 1.00 31.19 A N ATOM 382 CA LYS A 64 34.491 2.706 33.279 1.00 30.89 A C ATOM 383 CB LYS A 64 34.719 2.032 31.922 1.00 29.02 A C ATOM 384 CG LYS A 64 33.600 2.295 30.931 1.00 29.54 A C ATOM 385 CD LYS A 64 33.657 1.380 29.723 1.00 28.26 A C ATOM 386 CE LYS A 64 33.117 0.005 30.046 1.00 29.17 A C ATOM 387 NZ LYS A 64 32.990 0.829 28.825 1.00 27.96 A N ATOM 388 C LYS A 64 35.661 2.408 34.221 1.00 31.59 A C ATOM 389 O LYS A 64 35.926 1.256 34.559 1.00 31.45 A O ATOM 390 N ARG A 65 36.345 3.463 34.653 1.00 33.27 A N ATOM 391 CA ARG A 65 37.493 3.352 35.551 1.00 34.34 A C ATOM 392 CB ARG A 65 37.043 2.891 36.935 1.00 37.67 A C ATOM 393 CG ARG A 65 36.016 3.800 37.560 1.00 43.08 A C ATOM 394 CD ARG A 65 35.585 3.283 38.909 1.00 46.77 A C ATOM 395 NE ARG A 65 34.434 4.025 39.407 1.00 51.51 A N ATOM 396 CZ ARG A 65 33.927 3.888 40.628 1.00 53.49 A C ATOM 397 NH1 ARG A 65 34.474 3.032 41.484 1.00 54.10 A N ATOM 398 NH2 ARG A 65 32.872 4.608 40.993 1.00 54.47 A N ATOM 399 C ARG A 65 38.557 2.398 35.021 1.00 33.22 A C ATOM 400 O ARG A 65 39.086 1.576 35.770 1.00 32.38 A O ATOM 401 N LEU A 66 38.863 2.518 33.731 1.00 31.04 A N ATOM 402 CA LEU A 66 39.868 1.687 33.089 1.00 29.81 A C ATOM 403 CB LEU A 66 39.821 1.870 31.564 1.00 28.29 A C ATOM 404 CG LEU A 66 38.557 1.471 30.795 1.00 27.60 A C ATOM 405 CD1 LEU A 66 38.809 1.611 29.301 1.00 25.14 A C ATOM 406 CD2 LEU A 66 38.170 0.035 31.121 1.00 26.60 A C ATOM 407 C LEU A 66 41.272 2.020 33.597 1.00 30.22 A C ATOM 408 O LEU A 66 42.251 1.416 33.162 1.00 30.64 A O ATOM 409 N TYR A 67 41.375 2.980 34.514 1.00 30.84 A N ATOM 410 CA TYR A 67 42.677 3.365 35.055 1.00 32.60 A C ATOM 411 CB TYR A 67 42.688 4.846 35.438 1.00 33.43 A C ATOM 412 CG TYR A 67 41.642 5.226 36.463 1.00 36.96 A C ATOM 413 CD1 TYR A 67 41.809 4.922 37.810 1.00 37.60 A C ATOM 414 CE1 TYR A 67 40.833 5.254 38.745 1.00 39.51 A C ATOM 415 CD2 TYR A 67 40.468 5.875 36.077 1.00 38.20 A C ATOM 416 CE2 TYR A 67 39.488 6.211 37.004 1.00 38.78 A C ATOM 417 CZ TYR A 67 39.675 5.898 38.334 1.00 39.55 A C ATOM 418 OH TYR A 67 38.703 6.227 39.254 1.00 42.02 A O ATOM 419 C TYR A 67 43.037 2.534 36.270 1.00 33.52 A C ATOM 420 O TYR A 67 42.167 1.968 36.929 1.00 33.03 A O ATOM 421 N ASP A 68 44.327 2.459 36.567 1.00 35.06 A N ATOM 422 CA ASP A 68 44.765 1.699 37.721 1.00 36.88 A C ATOM 423 CB ASP A 68 46.146 1.100 37.476 1.00 37.88 A C ATOM 424 CG ASP A 68 46.658 0.340 38.674 1.00 38.95 A C ATOM 425 OD1 ASP A 68 45.863 −0.408 39.281 1.00 39.74 A O ATOM 426 OD2 ASP A 68 47.850 0.486 39.006 1.00 39.12 A O ATOM 427 C ASP A 68 44.795 2.593 38.952 1.00 38.61 A C ATOM 428 O ASP A 68 45.391 3.671 38.939 1.00 36.17 A O ATOM 429 N GLU A 69 44.138 2.138 40.013 1.00 41.45 A N ATOM 430 CA GLU A 69 44.068 2.889 41.261 1.00 44.18 A C ATOM 431 CB GLU A 69 43.392 2.042 42.345 1.00 47.21 A C ATOM 432 CG GLU A 69 41.883 1.953 42.222 1.00 50.20 A C ATOM 433 CD GLU A 69 41.238 3.322 42.249 1.00 52.69 A C ATOM 434 OE1 GLU A 69 41.619 4.132 43.126 1.00 53.29 A O ATOM 435 OE2 GLU A 69 40.352 3.586 41.403 1.00 54.11 A O ATOM 436 C GLU A 69 45.421 3.366 41.774 1.00 44.17 A C ATOM 437 O GLU A 69 45.615 4.553 42.023 1.00 43.71 A O ATOM 438 N LYS A 70 46.349 2.430 41.933 1.00 44.88 A N ATOM 439 CA LYS A 70 47.679 2.733 42.441 1.00 45.87 A C ATOM 440 CB LYS A 70 48.260 1.482 43.113 1.00 47.39 A C ATOM 441 CG LYS A 70 48.001 0.194 42.326 1.00 50.82 A C ATOM 442 CD LYS A 70 48.491 −1.060 43.052 1.00 52.70 A C ATOM 443 CE LYS A 70 48.068 −2.333 42.307 1.00 53.19 A C ATOM 444 NZ LYS A 70 48.468 −3.586 43.022 1.00 53.35 A N ATOM 445 C LYS A 70 48.639 3.255 41.376 1.00 45.61 A C ATOM 446 O LYS A 70 49.687 3.803 41.703 1.00 46.82 A O ATOM 447 N GLN A 71 48.284 3.079 40.107 1.00 45.07 A N ATOM 448 CA GLN A 71 49.123 3.539 38.995 1.00 44.59 A C ATOM 449 CB GLN A 71 49.852 2.352 38.357 1.00 45.81 A C ATOM 450 CG GLN A 71 51.048 2.754 37.525 1.00 48.21 A C ATOM 451 CD GLN A 71 52.085 3.500 38.343 1.00 49.07 A C ATOM 452 OE1 GLN A 71 53.008 4.103 37.795 1.00 49.90 A O ATOM 453 NE2 GLN A 71 51.940 3.458 39.665 1.00 49.28 A N ATOM 454 C GLN A 71 48.199 4.207 37.977 1.00 42.82 A C ATOM 455 O GLN A 71 48.023 3.733 36.851 1.00 41.55 A O ATOM 456 N GLN A 72 47.628 5.327 38.406 1.00 40.92 A N ATOM 457 CA GLN A 72 46.658 6.096 37.639 1.00 38.61 A C ATOM 458 CB GLN A 72 46.144 7.232 38.519 1.00 39.65 A C ATOM 459 CG GLN A 72 45.172 6.741 39.576 1.00 41.28 A C ATOM 460 CD GLN A 72 44.819 7.799 40.590 1.00 41.51 A C ATOM 461 OE1 GLN A 72 44.671 8.976 40.253 1.00 42.50 A O ATOM 462 NE2 GLN A 72 44.666 7.385 41.842 1.00 41.01 A N ATOM 463 C GLN A 72 46.948 6.631 36.247 1.00 35.53 A C ATOM 464 O GLN A 72 46.015 6.973 35.532 1.00 34.95 A O ATOM 465 N HIS A 73 48.210 6.712 35.847 1.00 33.43 A N ATOM 466 CA HIS A 73 48.508 7.216 34.512 1.00 31.21 A C ATOM 467 CB HIS A 73 49.841 7.975 34.514 1.00 32.43 A C ATOM 468 CG HIS A 73 51.039 7.111 34.753 1.00 35.52 A C ATOM 469 CD2 HIS A 73 51.615 6.683 35.901 1.00 36.10 A C ATOM 470 ND1 HIS A 73 51.796 6.588 33.725 1.00 36.24 A N ATOM 471 CE1 HIS A 73 52.788 5.876 34.230 1.00 36.90 A C ATOM 472 NE2 HIS A 73 52.701 5.918 35.548 1.00 37.46 A N ATOM 473 C HIS A 73 48.518 6.076 33.487 1.00 29.68 A C ATOM 474 O HIS A 73 48.681 6.297 32.278 1.00 28.72 A O ATOM 475 N ILE A 74 48.315 4.859 33.987 1.00 26.57 A N ATOM 476 CA ILE A 74 48.281 3.663 33.152 1.00 25.03 A C ATOM 477 CB ILE A 74 49.167 2.538 33.745 1.00 23.93 A C ATOM 478 CG2 ILE A 74 48.928 1.244 33.010 1.00 23.04 A C ATOM 479 CG1 ILE A 74 50.643 2.933 33.669 1.00 22.73 A C ATOM 480 CD1 ILE A 74 51.140 3.210 32.279 1.00 21.40 A C ATOM 481 C ILE A 74 46.856 3.135 33.017 1.00 24.39 A C ATOM 482 O ILE A 74 46.199 2.833 34.010 1.00 25.39 A O ATOM 483 N VAL A 75 46.387 3.025 31.782 1.00 23.12 A N ATOM 484 CA VAL A 75 45.048 2.527 31.506 1.00 22.39 A C ATOM 485 CB VAL A 75 44.413 3.306 30.319 1.00 21.87 A C ATOM 486 CG1 VAL A 75 43.016 2.784 30.024 1.00 19.40 A C ATOM 487 CG2 VAL A 75 44.376 4.777 30.629 1.00 21.46 A C ATOM 488 C VAL A 75 45.121 1.044 31.120 1.00 23.43 A C ATOM 489 O VAL A 75 46.031 0.631 30.396 1.00 24.66 A O ATOM 490 N TYR A 76 44.174 0.246 31.604 1.00 22.50 A N ATOM 491 CA TYR A 76 44.115 −1.173 31.256 1.00 22.83 A C ATOM 492 CB TYR A 76 44.106 −2.063 32.508 1.00 22.60 A C ATOM 493 CG TYR A 76 45.435 −2.130 33.237 1.00 23.26 A C ATOM 494 CD1 TYR A 76 45.728 −1.257 34.284 1.00 23.34 A C ATOM 495 CE1 TYR A 76 46.964 −1.291 34.928 1.00 24.06 A C ATOM 496 CD2 TYR A 76 46.414 −3.041 32.855 1.00 22.74 A C ATOM 497 CE2 TYR A 76 47.654 −3.083 33.493 1.00 23.63 A C ATOM 498 CZ TYR A 76 47.926 −2.207 34.526 1.00 23.89 A C ATOM 499 OH TYR A 76 49.159 −2.234 35.150 1.00 23.35 A O ATOM 500 C TYR A 76 42.825 −1.367 30.465 1.00 23.68 A C ATOM 501 O TYR A 76 41.727 −1.245 31.003 1.00 24.33 A O ATOM 502 N CYS A 77 42.953 −1.663 29.181 1.00 24.40 A N ATOM 503 CA CYS A 77 41.780 −1.826 28.342 1.00 26.23 A C ATOM 504 CB CYS A 77 41.778 −0.744 27.258 1.00 24.90 A C ATOM 505 SG CYS A 77 43.313 −0.601 26.325 1.00 17.76 A S ATOM 506 C CYS A 77 41.681 −3.193 27.692 1.00 29.22 A C ATOM 507 O CYS A 77 41.001 −3.354 26.676 1.00 29.98 A O ATOM 508 N SER A 78 42.337 −4.176 28.300 1.00 32.27 A N ATOM 509 CA SER A 78 42.366 −5.538 27.775 1.00 35.19 A C ATOM 510 CB SER A 78 43.016 −6.469 28.798 1.00 36.60 A C ATOM 511 OG SER A 78 43.133 −7.782 28.279 1.00 38.65 A O ATOM 512 C SER A 78 41.020 −6.119 27.340 1.00 36.61 A C ATOM 513 O SER A 78 40.777 −6.309 26.144 1.00 38.66 A O ATOM 514 N ASN A 79 40.145 −6.402 28.297 1.00 36.16 A N ATOM 515 CA ASN A 79 38.849 −6.982 27.961 1.00 37.19 A C ATOM 516 CB ASN A 79 38.340 −7.871 29.109 1.00 40.14 A C ATOM 517 CG ASN A 79 39.448 −8.682 29.769 1.00 42.98 A C ATOM 518 OD1 ASN A 79 40.255 −8.146 30.538 1.00 44.77 A O ATOM 519 ND2 ASN A 79 39.495 −9.978 29.471 1.00 42.57 A N ATOM 520 C ASN A 79 37.805 −5.909 27.669 1.00 36.10 A C ATOM 521 O ASN A 79 36.619 −6.105 27.936 1.00 36.61 A O ATOM 522 N ASP A 80 38.227 −4.787 27.101 1.00 33.75 A N ATOM 523 CA ASP A 80 37.283 −3.716 26.836 1.00 31.35 A C ATOM 524 CB ASP A 80 37.630 −2.513 27.708 1.00 33.87 A C ATOM 525 CG ASP A 80 36.563 −1.448 27.672 1.00 34.54 A C ATOM 526 OD1 ASP A 80 35.832 −1.315 28.679 1.00 35.54 A O ATOM 527 OD2 ASP A 80 36.453 −0.758 26.631 1.00 33.13 A O ATOM 528 C ASP A 80 37.229 −3.280 25.383 1.00 29.65 A C ATOM 529 O ASP A 80 38.182 −3.474 24.634 1.00 30.16 A O ATOM 530 N LEU A 81 36.109 −2.675 24.995 1.00 27.43 A N ATOM 531 CA LEU A 81 35.932 −2.200 23.629 1.00 26.30 A C ATOM 532 CB LEU A 81 34.605 −1.461 23.475 1.00 25.12 A C ATOM 533 CG LEU A 81 34.437 −0.778 22.111 1.00 23.81 A C ATOM 534 CD1 LEU A 81 34.714 −1.778 21.013 1.00 23.42 A C ATOM 535 CD2 LEU A 81 33.040 −0.213 21.971 1.00 23.74 A C ATOM 536 C LEU A 81 37.064 −1.278 23.194 1.00 26.69 A C ATOM 537 O LEU A 81 37.416 −1.235 22.010 1.00 27.34 A O ATOM 538 N LEU A 82 37.621 −0.529 24.144 1.00 25.53 A N ATOM 539 CA LEU A 82 38.717 0.375 23.827 1.00 24.07 A C ATOM 540 CB LEU A 82 39.087 1.217 25.047 1.00 20.46 A C ATOM 541 CG LEU A 82 40.236 2.202 24.829 1.00 18.75 A C ATOM 542 CD1 LEU A 82 39.913 3.166 23.689 1.00 17.60 A C ATOM 543 CD2 LEU A 82 40.488 2.955 26.112 1.00 18.82 A C ATOM 544 C LEU A 82 39.908 −0.468 23.376 1.00 25.11 A C ATOM 545 O LEU A 82 40.569 −0.149 22.381 1.00 26.18 A O ATOM 546 N GLY A 83 40.162 −1.553 24.105 1.00 24.69 A N ATOM 547 CA GLY A 83 41.249 −2.451 23.760 1.00 24.41 A C ATOM 548 C GLY A 83 41.170 −2.920 22.318 1.00 24.29 A C ATOM 549 O GLY A 83 42.196 −3.139 21.681 1.00 23.83 A O ATOM 550 N ASP A 84 39.958 −3.076 21.796 1.00 24.91 A N ATOM 551 CA ASP A 84 39.803 −3.503 20.410 1.00 27.77 A C ATOM 552 CB ASP A 84 38.386 −3.996 20.149 1.00 28.89 A C ATOM 553 CG ASP A 84 38.093 −5.295 20.837 1.00 31.01 A C ATOM 554 OD1 ASP A 84 39.042 −6.085 21.039 1.00 32.12 A O ATOM 555 OD2 ASP A 84 36.913 −5.532 21.160 1.00 31.66 A O ATOM 556 C ASP A 84 40.119 −2.392 19.410 1.00 28.99 A C ATOM 557 O ASP A 84 40.587 −2.664 18.297 1.00 29.29 A O ATOM 558 N LEU A 85 39.849 −1.146 19.799 1.00 28.12 A N ATOM 559 CA LEU A 85 40.104 −0.009 18.926 1.00 26.68 A C ATOM 560 CB LEU A 85 39.385 1.241 19.441 1.00 27.62 A C ATOM 561 CG LEU A 85 37.866 1.155 19.582 1.00 29.80 A C ATOM 562 CD1 LEU A 85 37.325 2.478 20.104 1.00 28.93 A C ATOM 563 CD2 LEU A 85 37.245 0.807 18.234 1.00 30.79 A C ATOM 564 C LEU A 85 41.592 0.268 18.866 1.00 25.94 A C ATOM 565 O LEU A 85 42.169 0.400 17.783 1.00 25.60 A O ATOM 566 N PHE A 86 42.208 0.354 20.042 1.00 24.28 A N ATOM 567 CA PHE A 86 43.636 0.633 20.143 1.00 23.89 A C ATOM 568 CB PHE A 86 43.980 1.113 21.563 1.00 23.07 A C ATOM 569 CG PHE A 86 43.601 2.548 21.837 1.00 21.05 A C ATOM 570 CD1 PHE A 86 42.858 3.284 20.914 1.00 19.37 A C ATOM 571 CD2 PHE A 86 43.992 3.165 23.021 1.00 20.29 A C ATOM 572 CE1 PHE A 86 42.509 4.612 21.167 1.00 18.94 A C ATOM 573 CE2 PHE A 86 43.649 4.496 23.285 1.00 20.32 A C ATOM 574 CZ PHE A 86 42.903 5.220 22.352 1.00 19.94 A C ATOM 575 C PHE A 86 44.498 −0.575 19.781 1.00 22.94 A C ATOM 576 O PHE A 86 45.550 −0.430 19.156 1.00 22.42 A O ATOM 577 N GLY A 87 44.049 −1.762 20.178 1.00 21.80 A N ATOM 578 CA GLY A 87 44.800 −2.969 19.881 1.00 20.71 A C ATOM 579 C GLY A 87 45.882 −3.270 20.904 1.00 18.88 A C ATOM 580 O GLY A 87 46.874 −3.940 20.604 1.00 17.62 A O ATOM 581 N VAL A 88 45.703 −2.769 22.119 1.00 17.60 A N ATOM 582 CA VAL A 88 46.685 −3.014 23.158 1.00 17.15 A C ATOM 583 CB VAL A 88 47.642 −1.815 23.356 1.00 16.00 A C ATOM 584 CG1 VAL A 88 48.277 −1.430 22.032 1.00 13.25 A C ATOM 585 CG2 VAL A 88 46.901 −0.652 23.975 1.00 15.16 A C ATOM 586 C VAL A 88 45.997 −3.290 24.472 1.00 17.59 A C ATOM 587 O VAL A 88 44.841 −2.922 24.667 1.00 18.43 A O ATOM 588 N PRO A 89 46.699 −3.966 25.390 1.00 18.50 A N ATOM 589 CD PRO A 89 47.976 −4.673 25.177 1.00 17.26 A C ATOM 590 CA PRO A 89 46.138 −4.287 26.705 1.00 17.37 A C ATOM 591 CB PRO A 89 46.958 −5.496 27.137 1.00 16.69 A C ATOM 592 CG PRO A 89 48.310 −5.170 26.575 1.00 17.70 A C ATOM 593 C PRO A 89 46.271 −3.115 27.677 1.00 17.13 A C ATOM 594 O PRO A 89 45.549 −3.042 28.669 1.00 18.98 A O ATOM 595 N SER A 90 47.196 −2.200 27.397 1.00 16.91 A N ATOM 596 CA SER A 90 47.394 −1.044 28.273 1.00 16.57 A C ATOM 597 CB SER A 90 48.002 −1.485 29.612 1.00 15.12 A C ATOM 598 OG SER A 90 49.329 −1.956 29.439 1.00 13.05 A O ATOM 599 C SER A 90 48.291 0.023 27.653 1.00 16.15 A C ATOM 600 O SER A 90 49.090 −0.261 26.764 1.00 17.41 A O ATOM 601 N PHE A 91 48.138 1.256 28.116 1.00 15.54 A N ATOM 602 CA PHE A 91 48.958 2.358 27.636 1.00 14.57 A C ATOM 603 CB PHE A 91 48.411 2.928 26.306 1.00 13.00 A C ATOM 604 CG PHE A 91 47.020 3.493 26.400 1.00 12.08 A C ATOM 605 CD1 PHE A 91 46.812 4.809 26.808 1.00 11.68 A C ATOM 606 CD2 PHE A 91 45.912 2.696 26.121 1.00 11.99 A C ATOM 607 CE1 PHE A 91 45.523 5.319 26.942 1.00 13.06 A C ATOM 608 CE2 PHE A 91 44.619 3.192 26.252 1.00 11.29 A C ATOM 609 CZ PHE A 91 44.421 4.509 26.666 1.00 12.95 A C ATOM 610 C PHE A 91 49.023 3.428 28.725 1.00 15.66 A C ATOM 611 O PHE A 91 48.287 3.370 29.720 1.00 15.88 A O ATOM 612 N SER A 92 49.938 4.375 28.548 1.00 16.43 A N ATOM 613 CA SER A 92 50.131 5.468 29.490 1.00 16.90 A C ATOM 614 CB SER A 92 51.619 5.639 29.781 1.00 15.41 A C ATOM 615 OG SER A 92 51.844 6.761 30.611 1.00 17.40 A O ATOM 616 C SER A 92 49.567 6.760 28.902 1.00 18.57 A C ATOM 617 O SER A 92 49.840 7.096 27.743 1.00 18.49 A O ATOM 618 N VAL A 93 48.783 7.480 29.702 1.00 20.07 A N ATOM 619 CA VAL A 93 48.183 8.734 29.257 1.00 20.40 A C ATOM 620 CB VAL A 93 47.061 9.195 30.207 1.00 20.59 A C ATOM 621 CG1 VAL A 93 45.998 8.112 30.324 1.00 18.90 A C ATOM 622 CG2 VAL A 93 47.645 9.543 31.572 1.00 19.55 A C ATOM 623 C VAL A 93 49.231 9.842 29.187 1.00 21.59 A C ATOM 624 O VAL A 93 48.921 10.980 28.851 1.00 21.46 A O ATOM 625 N LYS A 94 50.471 9.511 29.523 1.00 22.56 A N ATOM 626 CA LYS A 94 51.540 10.493 29.467 1.00 24.25 A C ATOM 627 CB LYS A 94 52.631 10.173 30.489 1.00 25.19 A C ATOM 628 CG LYS A 94 52.207 10.232 31.945 1.00 26.24 A C ATOM 629 CD LYS A 94 53.412 9.981 32.837 1.00 27.27 A C ATOM 630 CE LYS A 94 53.043 9.944 34.308 1.00 30.80 A C ATOM 631 NZ LYS A 94 54.257 9.744 35.158 1.00 32.53 A N ATOM 632 C LYS A 94 52.165 10.522 28.073 1.00 24.60 A C ATOM 633 O LYS A 94 52.767 11.521 27.683 1.00 26.90 A O ATOM 634 N GLU A 95 52.025 9.433 27.322 1.00 23.48 A N ATOM 635 CA GLU A 95 52.600 9.360 25.982 1.00 23.51 A C ATOM 636 CB GLU A 95 53.112 7.943 25.728 1.00 26.58 A C ATOM 637 CG GLU A 95 54.100 7.483 26.793 1.00 30.58 A C ATOM 638 CD GLU A 95 54.664 6.106 26.527 1.00 32.79 A C ATOM 639 OE1 GLU A 95 55.285 5.926 25.458 1.00 36.40 A O ATOM 640 OE2 GLU A 95 54.494 5.209 27.384 1.00 33.54 A O ATOM 641 C GLU A 95 51.583 9.770 24.929 1.00 21.33 A C ATOM 642 O GLU A 95 50.998 8.938 24.246 1.00 21.30 A O ATOM 643 N HIS A 96 51.404 11.076 24.795 1.00 19.78 A N ATOM 644 CA HIS A 96 50.435 11.643 23.877 1.00 19.53 A C ATOM 645 CB HIS A 96 50.438 13.163 24.018 1.00 22.57 A C ATOM 646 CG HIS A 96 50.141 13.631 25.410 1.00 26.45 A C ATOM 647 CD2 HIS A 96 50.220 12.988 26.600 1.00 27.85 A C ATOM 648 ND1 HIS A 96 49.701 14.906 25.694 1.00 27.37 A N ATOM 649 CE1 HIS A 96 49.517 15.026 26.997 1.00 26.91 A C ATOM 650 NE2 HIS A 96 49.824 13.878 27.569 1.00 28.84 A N ATOM 651 C HIS A 96 50.543 11.259 22.412 1.00 17.69 A C ATOM 652 O HIS A 96 49.536 10.931 21.792 1.00 16.79 A O ATOM 653 N ARG A 97 51.747 11.293 21.855 1.00 16.65 A N ATOM 654 CA ARG A 97 51.921 10.946 20.451 1.00 17.02 A C ATOM 655 CB ARG A 97 53.386 11.043 20.031 1.00 15.18 A C ATOM 656 CG ARG A 97 53.625 10.528 18.619 1.00 12.29 A C ATOM 657 CD ARG A 97 52.608 11.108 17.651 1.00 10.86 A C ATOM 658 NE ARG A 97 52.705 12.561 17.563 1.00 11.13 A N ATOM 659 CZ ARG A 97 51.782 13.343 17.005 1.00 12.71 A C ATOM 660 NH1 ARG A 97 50.678 12.817 16.480 1.00 7.43 A N ATOM 661 NH2 ARG A 97 51.968 14.659 16.966 1.00 11.79 A N ATOM 662 C ARG A 97 51.414 9.554 20.120 1.00 19.08 A C ATOM 663 O ARG A 97 50.768 9.357 19.086 1.00 20.69 A O ATOM 664 N LYS A 98 51.710 8.589 20.985 1.00 18.63 A N ATOM 665 CA LYS A 98 51.264 7.228 20.749 1.00 18.59 A C ATOM 666 CB LYS A 98 51.935 6.280 21.734 1.00 18.48 A C ATOM 667 CG LYS A 98 53.447 6.253 21.566 1.00 19.06 A C ATOM 668 CD LYS A 98 54.096 5.206 22.447 1.00 19.89 A C ATOM 669 CE LYS A 98 55.607 5.329 22.415 1.00 19.38 A C ATOM 670 NZ LYS A 98 56.239 4.302 23.281 1.00 20.88 A N ATOM 671 C LYS A 98 49.746 7.089 20.807 1.00 19.21 A C ATOM 672 O LYS A 98 49.150 6.420 19.955 1.00 20.63 A O ATOM 673 N ILE A 99 49.108 7.714 21.791 1.00 18.36 A N ATOM 674 CA ILE A 99 47.651 7.634 21.883 1.00 17.63 A C ATOM 675 CB ILE A 99 47.124 8.421 23.082 1.00 16.98 A C ATOM 676 CG2 ILE A 99 45.647 8.750 22.882 1.00 16.18 A C ATOM 677 CG1 ILE A 99 47.363 7.617 24.358 1.00 15.24 A C ATOM 678 CD1 ILE A 99 46.946 8.332 25.608 1.00 14.96 A C ATOM 679 C ILE A 99 47.019 8.189 20.609 1.00 17.52 A C ATOM 680 O ILE A 99 46.097 7.608 20.051 1.00 17.08 A O ATOM 681 N TYR A 100 47.527 9.324 20.154 1.00 17.72 A N ATOM 682 CA TYR A 100 47.029 9.945 18.945 1.00 17.07 A C ATOM 683 CB TYR A 100 47.857 11.194 18.626 1.00 17.38 A C ATOM 684 CG TYR A 100 47.175 12.490 18.997 1.00 18.41 A C ATOM 685 CD1 TYR A 100 46.833 12.765 20.323 1.00 18.50 A C ATOM 686 CE1 TYR A 100 46.137 13.921 20.661 1.00 18.48 A C ATOM 687 CD2 TYR A 100 46.808 13.414 18.014 1.00 17.87 A C ATOM 688 CE2 TYR A 100 46.107 14.577 18.339 1.00 19.07 A C ATOM 689 CZ TYR A 100 45.771 14.822 19.667 1.00 19.64 A C ATOM 690 OH TYR A 100 45.059 15.953 20.002 1.00 18.84 A O ATOM 691 C TYR A 100 47.064 8.990 17.752 1.00 17.45 A C ATOM 692 O TYR A 100 46.050 8.760 17.093 1.00 17.05 A O ATOM 693 N THR A 101 48.228 8.419 17.471 1.00 17.36 A N ATOM 694 CA THR A 101 48.323 7.536 16.323 1.00 18.06 A C ATOM 695 CB THR A 101 49.786 7.081 16.069 1.00 18.65 A C ATOM 696 OG1 THR A 101 50.051 5.875 16.783 1.00 21.69 A O ATOM 697 CG2 THR A 101 50.760 8.147 16.522 1.00 16.26 A C ATOM 698 C THR A 101 47.412 6.329 16.504 1.00 16.52 A C ATOM 699 O THR A 101 46.894 5.768 15.534 1.00 16.44 A O ATOM 700 N MET A 102 47.199 5.954 17.758 1.00 15.80 A N ATOM 701 CA MET A 102 46.344 4.819 18.089 1.00 14.43 A C ATOM 702 CB MET A 102 46.515 4.484 19.572 1.00 13.64 A C ATOM 703 CG MET A 102 46.355 3.027 19.941 1.00 13.28 A C ATOM 704 SD MET A 102 47.540 2.468 21.221 1.00 10.86 A S ATOM 705 CE MET A 102 47.349 3.728 22.494 1.00 6.45 A C ATOM 706 C MET A 102 44.907 5.235 17.772 1.00 13.90 A C ATOM 707 O MET A 102 44.106 4.432 17.301 1.00 14.80 A O ATOM 708 N ILE A 103 44.590 6.503 18.017 1.00 13.28 A N ATOM 709 CA ILE A 103 43.256 7.028 17.725 1.00 13.02 A C ATOM 710 CB ILE A 103 43.004 8.396 18.428 1.00 10.40 A C ATOM 711 CG2 ILE A 103 41.697 9.007 17.940 1.00 7.72 A C ATOM 712 CG1 ILE A 103 42.974 8.215 19.942 1.00 11.39 A C ATOM 713 CD1 ILE A 103 42.806 9.524 20.725 1.00 11.61 A C ATOM 714 C ILE A 103 43.082 7.232 16.210 1.00 13.88 A C ATOM 715 O ILE A 103 42.009 6.975 15.664 1.00 13.40 A O ATOM 716 N TYR A 104 44.138 7.685 15.538 1.00 13.99 A N ATOM 717 CA TYR A 104 44.071 7.933 14.097 1.00 17.99 A C ATOM 718 CB TYR A 104 45.422 8.430 13.578 1.00 16.14 A C ATOM 719 CG TYR A 104 45.621 9.917 13.746 1.00 15.96 A C ATOM 720 CD1 TYR A 104 46.759 10.425 14.378 1.00 15.68 A C ATOM 721 CE1 TYR A 104 46.943 11.795 14.524 1.00 14.23 A C ATOM 722 CD2 TYR A 104 44.673 10.819 13.267 1.00 15.02 A C ATOM 723 CE2 TYR A 104 44.846 12.182 13.405 1.00 14.75 A C ATOM 724 CZ TYR A 104 45.981 12.667 14.031 1.00 15.94 A C ATOM 725 OH TYR A 104 46.155 14.028 14.143 1.00 17.64 A O ATOM 726 C TYR A 104 43.602 6.760 13.234 1.00 20.21 A C ATOM 727 O TYR A 104 42.964 6.962 12.199 1.00 21.85 A O ATOM 728 N ARG A 105 43.907 5.538 13.655 1.00 21.85 A N ATOM 729 CA ARG A 105 43.506 4.371 12.885 1.00 21.76 A C ATOM 730 CB ARG A 105 44.272 3.138 13.361 1.00 22.75 A C ATOM 731 CG ARG A 105 45.731 3.143 12.953 1.00 23.10 A C ATOM 732 CD ARG A 105 46.356 1.779 13.162 1.00 23.66 A C ATOM 733 NE ARG A 105 46.518 1.474 14.573 1.00 22.31 A N ATOM 734 CZ ARG A 105 47.674 1.540 15.217 1.00 22.19 A C ATOM 735 NH1 ARG A 105 48.770 1.897 14.565 1.00 18.18 A N ATOM 736 NH2 ARG A 105 47.726 1.255 16.517 1.00 24.90 A N ATOM 737 C ARG A 105 42.010 4.099 12.949 1.00 22.18 A C ATOM 738 O ARG A 105 41.471 3.381 12.106 1.00 23.20 A O ATOM 739 N ASN A 106 41.333 4.677 13.936 1.00 20.61 A N ATOM 740 CA ASN A 106 39.903 4.452 14.074 1.00 18.60 A C ATOM 741 CB ASN A 106 39.547 4.250 15.538 1.00 16.23 A C ATOM 742 CG ASN A 106 40.187 3.023 16.107 1.00 15.21 A C ATOM 743 OD1 ASN A 106 41.382 3.005 16.389 1.00 14.14 A O ATOM 744 ND2 ASN A 106 39.400 1.973 16.261 1.00 16.32 A N ATOM 745 C ASN A 106 39.060 5.565 13.501 1.00 18.34 A C ATOM 746 O ASN A 106 37.908 5.746 13.895 1.00 18.15 A O ATOM 747 N LEU A 107 39.620 6.306 12.558 1.00 17.64 A N ATOM 748 CA LEU A 107 38.875 7.401 11.973 1.00 18.35 A C ATOM 749 CB LEU A 107 38.888 8.604 12.929 1.00 16.91 A C ATOM 750 CG LEU A 107 40.265 9.202 13.273 1.00 18.09 A C ATOM 751 CD1 LEU A 107 40.853 9.969 12.077 1.00 14.35 A C ATOM 752 CD2 LEU A 107 40.114 10.138 14.470 1.00 17.65 A C ATOM 753 C LEU A 107 39.449 7.816 10.639 1.00 18.05 A C ATOM 754 O LEU A 107 40.510 7.355 10.239 1.00 17.80 A O ATOM 755 N VAL A 108 38.733 8.708 9.968 1.00 18.61 A N ATOM 756 CA VAL A 108 39.161 9.247 8.694 1.00 19.37 A C ATOM 757 CB VAL A 108 38.118 8.985 7.596 1.00 17.78 A C ATOM 758 CG1 VAL A 108 38.562 9.636 6.300 1.00 16.53 A C ATOM 759 CG2 VAL A 108 37.939 7.495 7.401 1.00 18.03 A C ATOM 760 C VAL A 108 39.322 10.755 8.867 1.00 20.94 A C ATOM 761 O VAL A 108 38.406 11.433 9.324 1.00 20.81 A O ATOM 762 N VAL A 109 40.495 11.275 8.517 1.00 23.78 A N ATOM 763 CA VAL A 109 40.761 12.710 8.611 1.00 26.16 A C ATOM 764 CB VAL A 109 42.278 13.011 8.516 1.00 22.72 A C ATOM 765 CG1 VAL A 109 42.504 14.496 8.395 1.00 22.45 A C ATOM 766 CG2 VAL A 109 42.997 12.480 9.737 1.00 21.93 A C ATOM 767 C VAL A 109 40.043 13.448 7.470 1.00 30.24 A C ATOM 768 O VAL A 109 40.298 13.187 6.287 1.00 30.49 A O ATOM 769 N VAL A 110 39.138 14.355 7.832 1.00 33.46 A N ATOM 770 CA VAL A 110 38.397 15.138 6.850 1.00 36.26 A C ATOM 771 CB VAL A 110 37.210 15.872 7.489 1.00 34.68 A C ATOM 772 CG1 VAL A 110 36.511 16.703 6.448 1.00 32.97 A C ATOM 773 CG2 VAL A 110 36.252 14.882 8.103 1.00 33.70 A C ATOM 774 C VAL A 110 39.314 16.191 6.246 1.00 40.32 A C ATOM 775 O VAL A 110 39.808 17.071 6.952 1.00 40.87 A O ATOM 776 N ASN A 111 39.543 16.091 4.940 1.00 45.40 A N ATOM 777 CA ASN A 111 40.398 17.040 4.226 1.00 49.94 A C ATOM 778 CB ASN A 111 41.073 16.364 3.019 1.00 50.86 A C ATOM 779 CG ASN A 111 42.382 15.675 3.386 1.00 52.48 A C ATOM 780 OD1 ASN A 111 43.283 16.296 3.956 1.00 53.64 A O ATOM 781 ND2 ASN A 111 42.495 14.393 3.052 1.00 51.26 A N ATOM 782 C ASN A 111 39.604 18.262 3.753 1.00 51.80 A C ATOM 783 O ASN A 111 39.362 18.363 2.526 1.00 53.21 A O ATOM 784 OXT ASN A 111 39.228 19.098 4.615 1.00 52.33 A O ATOM 785 C GLY B 16 53.854 −21.456 19.940 1.00 68.34 B C ATOM 786 O GLY B 16 54.218 −22.369 20.690 1.00 69.67 B O ATOM 787 N GLY B 16 56.279 −20.814 19.623 1.00 65.62 B N ATOM 788 CA GLY B 16 54.867 −20.597 19.196 1.00 67.24 B C ATOM 789 N SER B 17 52.576 −21.151 19.730 1.00 67.70 B N ATOM 790 CA SER B 17 51.454 −21.865 20.345 1.00 67.10 B C ATOM 791 CB SER B 17 51.431 −21.641 21.858 1.00 67.49 B C ATOM 792 OG SER B 17 52.590 −22.178 22.475 1.00 68.01 B O ATOM 793 C SER B 17 50.200 −21.284 19.691 1.00 66.62 B C ATOM 794 O SER B 17 50.268 −20.198 19.108 1.00 67.53 B O ATOM 795 N GLN B 18 49.064 −21.984 19.777 1.00 65.03 B N ATOM 796 CA GLN B 18 47.833 −21.519 19.117 1.00 62.52 B C ATOM 797 CB GLN B 18 47.417 −20.132 19.614 1.00 63.01 B C ATOM 798 CG GLN B 18 46.783 −20.084 20.983 1.00 63.28 B C ATOM 799 CD GLN B 18 46.536 −18.655 21.437 1.00 64.15 B C ATOM 800 OE1 GLN B 18 45.964 −17.847 20.702 1.00 64.39 B O ATOM 801 NE2 GLN B 18 46.967 −18.337 22.652 1.00 64.33 B N ATOM 802 C GLN B 18 48.190 −21.421 17.633 1.00 60.63 B C ATOM 803 O GLN B 18 47.364 −21.081 16.784 1.00 59.42 B O ATOM 804 N ILE B 19 49.455 −21.721 17.360 1.00 58.87 B N ATOM 805 CA ILE B 19 50.046 −21.693 16.039 1.00 57.04 B C ATOM 806 CB ILE B 19 51.187 −20.647 15.978 1.00 57.12 B C ATOM 807 CG2 ILE B 19 51.857 −20.675 14.620 1.00 57.22 B C ATOM 808 CG1 ILE B 19 50.635 −19.253 16.284 1.00 56.68 B C ATOM 809 CD1 ILE B 19 49.517 −18.819 15.365 1.00 55.99 B C ATOM 810 C ILE B 19 50.625 −23.085 15.792 1.00 55.95 B C ATOM 811 O ILE B 19 51.432 −23.583 16.578 1.00 55.35 B O ATOM 812 N PRO B 20 50.202 −23.736 14.700 1.00 54.93 B N ATOM 813 CD PRO B 20 49.131 −23.312 13.782 1.00 54.65 B C ATOM 814 CA PRO B 20 50.676 −25.074 14.344 1.00 53.57 B C ATOM 815 CB PRO B 20 50.014 −25.310 12.995 1.00 53.84 B C ATOM 816 CG PRO B 20 48.702 −24.629 13.181 1.00 54.58 B C ATOM 817 C PRO B 20 52.196 −25.214 14.286 1.00 52.28 B C ATOM 818 O PRO B 20 52.910 −24.281 13.911 1.00 51.94 B O ATOM 819 N ALA B 21 52.677 −26.395 14.662 1.00 50.58 B N ATOM 820 CA ALA B 21 54.103 −26.685 14.663 1.00 48.29 B C ATOM 821 CB ALA B 21 54.338 −28.144 15.065 1.00 47.65 B C ATOM 822 C ALA B 21 54.706 −26.412 13.287 1.00 46.77 B C ATOM 823 O ALA B 21 55.853 −25.967 13.181 1.00 46.51 B O ATOM 824 N SER B 22 53.933 −26.680 12.236 1.00 44.16 B N ATOM 825 CA SER B 22 54.407 −26.458 10.878 1.00 41.95 B C ATOM 826 CB SER B 22 53.314 −26.804 9.868 1.00 42.69 B C ATOM 827 OG SER B 22 53.760 −26.560 8.545 1.00 42.99 B O ATOM 828 C SER B 22 54.822 −25.007 10.699 1.00 40.70 B C ATOM 829 O SER B 22 55.787 −24.714 9.998 1.00 40.64 B O ATOM 830 N GLU B 23 54.091 −24.106 11.348 1.00 38.86 B N ATOM 831 CA GLU B 23 54.364 −22.676 11.264 1.00 37.00 B C ATOM 832 CB GLU B 23 53.078 −21.892 11.557 1.00 37.30 B C ATOM 833 CG GLU B 23 53.240 −20.380 11.631 1.00 38.01 B C ATOM 834 CD GLU B 23 51.911 −19.648 11.519 1.00 38.73 B C ATOM 835 OE1 GLU B 23 50.882 −20.207 11.961 1.00 38.07 B O ATOM 836 OE2 GLU B 23 51.896 −18.511 10.996 1.00 38.22 B O ATOM 837 C GLU B 23 55.494 −22.211 12.185 1.00 35.56 B C ATOM 838 O GLU B 23 56.199 −21.260 11.860 1.00 35.70 B O ATOM 839 N GLN B 24 55.667 −22.875 13.326 1.00 34.12 B N ATOM 840 CA GLN B 24 56.727 −22.514 14.272 1.00 32.95 B C ATOM 841 CB GLN B 24 56.644 −23.344 15.540 1.00 33.15 B C ATOM 842 CG GLN B 24 55.371 −23.272 16.311 1.00 35.12 B C ATOM 843 CD GLN B 24 55.483 −24.101 17.563 1.00 37.66 B C ATOM 844 OE1 GLN B 24 55.813 −25.287 17.505 1.00 40.52 B O ATOM 845 NE2 GLN B 24 55.229 −23.488 18.706 1.00 38.27 B N ATOM 846 C GLN B 24 58.110 −22.766 13.693 1.00 32.72 B C ATOM 847 O GLN B 24 59.076 −22.083 14.045 1.00 31.93 B O ATOM 848 N GLU B 25 58.202 −23.771 12.826 1.00 32.31 B N ATOM 849 CA GLU B 25 59.470 −24.143 12.216 1.00 31.68 B C ATOM 850 CB GLU B 25 59.485 −25.656 11.931 1.00 32.59 B C ATOM 851 CG GLU B 25 59.233 −26.531 13.173 1.00 34.22 B C ATOM 852 CD GLU B 25 60.296 −26.368 14.262 1.00 34.77 B C ATOM 853 OE1 GLU B 25 59.978 −26.561 15.454 1.00 36.34 B O ATOM 854 OE2 GLU B 25 61.456 −26.059 13.935 1.00 36.40 B O ATOM 855 C GLU B 25 59.804 −23.353 10.949 1.00 30.50 B C ATOM 856 O GLU B 25 60.852 −23.565 10.340 1.00 29.64 B O ATOM 857 N THR B 26 58.922 −22.439 10.557 1.00 29.23 B N ATOM 858 CA THR B 26 59.166 −21.624 9.373 1.00 30.19 B C ATOM 859 CB THR B 26 58.142 −20.489 9.259 1.00 31.00 B C ATOM 860 OG1 THR B 26 56.822 −21.038 9.227 1.00 33.70 B O ATOM 861 CG2 THR B 26 58.382 −19.684 7.997 1.00 31.13 B C ATOM 862 C THR B 26 60.560 −21.001 9.468 1.00 30.70 B C ATOM 863 O THR B 26 60.975 −20.554 10.539 1.00 31.04 B O ATOM 864 N LEU B 27 61.277 −20.965 8.347 1.00 30.93 B N ATOM 865 CA LEU B 27 62.622 −20.402 8.328 1.00 29.18 B C ATOM 866 CB LEU B 27 63.471 −21.120 7.284 1.00 31.12 B C ATOM 867 CG LEU B 27 64.970 −21.070 7.576 1.00 33.61 B C ATOM 868 CD1 LEU B 27 65.243 −21.802 8.889 1.00 32.80 B C ATOM 869 CD2 LEU B 27 65.753 −21.706 6.433 1.00 34.54 B C ATOM 870 C LEU B 27 62.559 −18.913 8.013 1.00 27.91 B C ATOM 871 O LEU B 27 61.866 −18.493 7.089 1.00 27.36 B O ATOM 872 N VAL B 28 63.288 −18.109 8.775 1.00 26.63 B N ATOM 873 CA VAL B 28 63.256 −16.670 8.561 1.00 25.38 B C ATOM 874 CB VAL B 28 62.249 −16.018 9.530 1.00 25.06 B C ATOM 875 CG1 VAL B 28 60.848 −16.521 9.245 1.00 22.93 B C ATOM 876 CG2 VAL B 28 62.626 −16.347 10.967 1.00 25.37 B C ATOM 877 C VAL B 28 64.606 −15.968 8.714 1.00 25.60 B C ATOM 878 O VAL B 28 65.554 −16.523 9.266 1.00 24.51 B O ATOM 879 N ARG B 29 64.671 −14.740 8.202 1.00 26.32 B N ATOM 880 CA ARG B 29 65.862 −13.893 8.265 1.00 26.36 B C ATOM 881 CB ARG B 29 66.417 −13.640 6.865 1.00 29.44 B C ATOM 882 CG ARG B 29 67.420 −14.653 6.377 1.00 35.76 B C ATOM 883 CD ARG B 29 67.752 −14.431 4.895 1.00 40.93 B C ATOM 884 NE ARG B 29 68.922 −15.209 4.488 1.00 44.00 B N ATOM 885 CZ ARG B 29 70.157 −14.969 4.923 1.00 45.03 B C ATOM 886 NH1 ARG B 29 70.377 −13.970 5.773 1.00 44.48 B N ATOM 887 NH2 ARG B 29 71.169 −15.730 4.521 1.00 46.18 B N ATOM 888 C ARG B 29 65.458 −12.550 8.868 1.00 25.24 B C ATOM 889 O ARG B 29 64.973 −11.672 8.152 1.00 26.08 B O ATOM 890 N PRO B 30 65.642 −12.372 10.191 1.00 22.82 B N ATOM 891 CD PRO B 30 66.109 −13.336 11.200 1.00 21.19 B C ATOM 892 CA PRO B 30 65.275 −11.108 10.830 1.00 21.09 B C ATOM 893 CB PRO B 30 65.777 −11.295 12.256 1.00 18.84 B C ATOM 894 CG PRO B 30 65.582 −12.732 12.478 1.00 19.25 B C ATOM 895 C PRO B 30 65.920 −9.905 10.148 1.00 21.41 B C ATOM 896 O PRO B 30 67.023 −10.002 9.613 1.00 21.85 B O ATOM 897 N LYS B 31 65.224 −8.774 10.163 1.00 20.86 B N ATOM 898 CA LYS B 31 65.754 −7.561 9.572 1.00 20.51 B C ATOM 899 CB LYS B 31 64.627 −6.584 9.271 1.00 20.10 B C ATOM 900 CG LYS B 31 63.744 −7.089 8.159 1.00 21.08 B C ATOM 901 CD LYS B 31 62.678 −6.107 7.802 1.00 22.40 B C ATOM 902 CE LYS B 31 61.801 −6.685 6.728 1.00 24.64 B C ATOM 903 NZ LYS B 31 60.672 −5.777 6.428 1.00 28.16 B N ATOM 904 C LYS B 31 66.755 −6.969 10.542 1.00 20.98 B C ATOM 905 O LYS B 31 66.823 −7.376 11.691 1.00 22.03 B O ATOM 906 N PRO B 32 67.543 −5.993 10.094 1.00 21.99 B N ATOM 907 CD PRO B 32 67.505 −5.349 8.769 1.00 20.88 B C ATOM 908 CA PRO B 32 68.552 −5.367 10.949 1.00 22.11 B C ATOM 909 CB PRO B 32 68.893 −4.093 10.190 1.00 23.23 B C ATOM 910 CG PRO B 32 68.806 −4.569 8.758 1.00 22.91 B C ATOM 911 C PRO B 32 68.231 −5.114 12.416 1.00 22.72 B C ATOM 912 O PRO B 32 69.026 −5.485 13.282 1.00 23.53 B O ATOM 913 N LEU B 33 67.090 −4.500 12.719 1.00 22.94 B N ATOM 914 CA LEU B 33 66.772 −4.221 14.123 1.00 22.90 B C ATOM 915 CB LEU B 33 65.696 −3.143 14.235 1.00 24.77 B C ATOM 916 CG LEU B 33 66.288 −1.756 14.535 1.00 28.92 B C ATOM 917 CD1 LEU B 33 67.420 −1.399 13.547 1.00 26.95 B C ATOM 918 CD2 LEU B 33 65.170 −0.724 14.473 1.00 31.12 B C ATOM 919 C LEU B 33 66.393 −5.424 14.966 1.00 21.68 B C ATOM 920 O LEU B 33 66.896 −5.577 16.075 1.00 21.88 B O ATOM 921 N LEU B 34 65.506 −6.274 14.462 1.00 20.94 B N ATOM 922 CA LEU B 34 65.133 −7.468 15.209 1.00 19.68 B C ATOM 923 CB LEU B 34 64.048 −8.250 14.473 1.00 18.05 B C ATOM 924 CG LEU B 34 63.758 −9.664 14.981 1.00 15.31 B C ATOM 925 CD1 LEU B 34 63.339 −9.643 16.437 1.00 13.94 B C ATOM 926 CD2 LEU B 34 62.678 −10.274 14.128 1.00 13.57 B C ATOM 927 C LEU B 34 66.381 −8.340 15.363 1.00 20.89 B C ATOM 928 O LEU B 34 66.583 −8.968 16.402 1.00 20.95 B O ATOM 929 N LEU B 35 67.218 −8.363 14.327 1.00 20.45 B N ATOM 930 CA LEU B 35 68.447 −9.149 14.347 1.00 22.34 B C ATOM 931 CB LEU B 35 69.182 −9.022 13.003 1.00 22.21 B C ATOM 932 CG LEU B 35 70.410 −9.892 12.701 1.00 21.01 B C ATOM 933 CD1 LEU B 35 71.607 −9.401 13.484 1.00 23.40 B C ATOM 934 CD2 LEU B 35 70.104 −11.338 13.026 1.00 20.20 B C ATOM 935 C LEU B 35 69.342 −8.687 15.492 1.00 23.56 B C ATOM 936 O LEU B 35 69.819 −9.506 16.282 1.00 25.34 B O ATOM 937 N LYS B 36 69.567 −7.380 15.590 1.00 24.88 B N ATOM 938 CA LYS B 36 70.400 −6.841 16.665 1.00 26.33 B C ATOM 939 CB LYS B 36 70.529 −5.318 16.553 1.00 28.76 B C ATOM 940 CG LYS B 36 71.228 −4.689 17.758 1.00 33.99 B C ATOM 941 CD LYS B 36 71.153 −3.159 17.762 1.00 38.12 B C ATOM 942 CE LYS B 36 72.023 −2.540 16.661 1.00 39.99 B C ATOM 943 NZ LYS B 36 71.900 −1.052 16.616 1.00 40.20 B N ATOM 944 C LYS B 36 69.757 −7.187 18.001 1.00 25.07 B C ATOM 945 O LYS B 36 70.433 −7.541 18.964 1.00 25.56 B O ATOM 946 N LEU B 37 68.438 −7.071 18.039 1.00 23.72 B N ATOM 947 CA LEU B 37 67.659 −7.362 19.228 1.00 23.05 B C ATOM 948 CB LEU B 37 66.179 −7.198 18.894 1.00 23.27 B C ATOM 949 CG LEU B 37 65.156 −6.988 20.002 1.00 22.39 B C ATOM 950 CD1 LEU B 37 65.148 −8.176 20.938 1.00 22.88 B C ATOM 951 CD2 LEU B 37 65.485 −5.712 20.724 1.00 21.97 B C ATOM 952 C LEU B 37 67.941 −8.798 19.679 1.00 23.41 B C ATOM 953 O LEU B 37 68.180 −9.066 20.860 1.00 22.57 B O ATOM 954 N LEU B 38 67.921 −9.721 18.724 1.00 22.64 B N ATOM 955 CA LEU B 38 68.158 −11.121 19.032 1.00 21.31 B C ATOM 956 CB LEU B 38 67.838 −11.988 17.808 1.00 18.85 B C ATOM 957 CG LEU B 38 66.368 −11.934 17.379 1.00 17.25 B C ATOM 958 CD1 LEU B 38 66.178 −12.760 16.123 1.00 16.90 B C ATOM 959 CD2 LEU B 38 65.462 −12.430 18.509 1.00 12.89 B C ATOM 960 C LEU B 38 69.588 −11.349 19.496 1.00 22.29 B C ATOM 961 O LEU B 38 69.815 −11.935 20.555 1.00 21.71 B O ATOM 962 N LYS B 39 70.554 −10.878 18.713 1.00 22.57 B N ATOM 963 CA LYS B 39 71.952 −11.053 19.082 1.00 22.22 B C ATOM 964 CB LYS B 39 72.871 −10.518 17.978 1.00 21.13 B C ATOM 965 CG LYS B 39 72.856 −11.376 16.731 1.00 21.02 B C ATOM 966 CD LYS B 39 73.951 −10.999 15.757 1.00 20.77 B C ATOM 967 CE LYS B 39 73.888 −11.897 14.531 1.00 22.57 B C ATOM 968 NZ LYS B 39 74.967 −11.621 13.550 1.00 24.14 B N ATOM 969 C LYS B 39 72.292 −10.390 20.410 1.00 22.10 B C ATOM 970 O LYS B 39 73.286 −10.739 21.046 1.00 23.45 B O ATOM 971 N SER B 40 71.462 −9.445 20.840 1.00 21.94 B N ATOM 972 CA SER B 40 71.711 −8.748 22.093 1.00 21.68 B C ATOM 973 CB SER B 40 70.809 −7.526 22.206 1.00 22.53 B C ATOM 974 OG SER B 40 69.479 −7.917 22.486 1.00 27.18 B O ATOM 975 C SER B 40 71.486 −9.645 23.305 1.00 21.15 B C ATOM 976 O SER B 40 71.920 −9.319 24.401 1.00 20.79 B O ATOM 977 N VAL B 41 70.789 −10.762 23.116 1.00 20.81 B N ATOM 978 CA VAL B 41 70.533 −11.690 24.213 1.00 20.10 B C ATOM 979 CB VAL B 41 69.012 −11.875 24.469 1.00 20.10 B C ATOM 980 CG1 VAL B 41 68.448 −10.651 25.163 1.00 20.00 B C ATOM 981 CG2 VAL B 41 68.285 −12.117 23.159 1.00 20.21 B C ATOM 982 C VAL B 41 71.165 −13.067 23.999 1.00 19.56 B C ATOM 983 O VAL B 41 70.695 −14.069 24.539 1.00 18.39 B O ATOM 984 N GLY B 42 72.224 −13.120 23.198 1.00 19.73 B N ATOM 985 CA GLY B 42 72.898 −14.385 22.981 1.00 20.77 B C ATOM 986 C GLY B 42 72.691 −15.090 21.658 1.00 22.17 B C ATOM 987 O GLY B 42 73.391 −16.062 21.379 1.00 24.42 B O ATOM 988 N ALA B 43 71.738 −14.645 20.847 1.00 22.24 B N ATOM 989 CA ALA B 43 71.522 −15.287 19.554 1.00 22.66 B C ATOM 990 CB ALA B 43 70.320 −14.680 18.849 1.00 20.93 B C ATOM 991 C ALA B 43 72.769 −15.073 18.715 1.00 23.43 B C ATOM 992 O ALA B 43 73.501 −14.103 18.925 1.00 23.42 B O ATOM 993 N GLN B 44 73.020 −15.976 17.772 1.00 25.27 B N ATOM 994 CA GLN B 44 74.184 −15.839 16.907 1.00 27.42 B C ATOM 995 CB GLN B 44 75.422 −16.377 17.613 1.00 29.51 B C ATOM 996 CG GLN B 44 75.181 −17.618 18.411 1.00 31.44 B C ATOM 997 CD GLN B 44 76.005 −17.618 19.673 1.00 35.21 B C ATOM 998 OE1 GLN B 44 76.221 −18.664 20.286 1.00 38.33 B O ATOM 999 NE2 GLN B 44 76.468 −16.436 20.078 1.00 33.71 B N ATOM 1000 C GLN B 44 74.060 −16.454 15.519 1.00 27.16 B C ATOM 1001 O GLN B 44 74.969 −17.126 15.036 1.00 28.13 B O ATOM 1002 N LYS B 45 72.926 −16.205 14.879 1.00 26.81 B N ATOM 1003 CA LYS B 45 72.670 −16.683 13.534 1.00 25.44 B C ATOM 1004 CB LYS B 45 71.723 −17.884 13.555 1.00 24.61 B C ATOM 1005 CG LYS B 45 72.275 −19.113 14.259 1.00 23.83 B C ATOM 1006 CD LYS B 45 71.387 −20.345 14.042 1.00 21.51 B C ATOM 1007 CE LYS B 45 70.025 −20.201 14.700 1.00 21.68 B C ATOM 1008 NZ LYS B 45 69.171 −21.397 14.466 1.00 21.07 B N ATOM 1009 C LYS B 45 72.022 −15.526 12.786 1.00 25.54 B C ATOM 1010 O LYS B 45 71.616 −14.538 13.387 1.00 23.91 B O ATOM 1011 N ASP B 46 71.944 −15.637 11.470 1.00 26.59 B N ATOM 1012 CA ASP B 46 71.323 −14.595 10.681 1.00 28.75 B C ATOM 1013 CB ASP B 46 72.216 −14.197 9.503 1.00 31.00 B C ATOM 1014 CG ASP B 46 73.525 −13.573 9.952 1.00 34.10 B C ATOM 1015 OD1 ASP B 46 73.573 −13.029 11.081 1.00 34.46 B O ATOM 1016 OD2 ASP B 46 74.506 −13.614 9.174 1.00 37.45 B O ATOM 1017 C ASP B 46 69.989 −15.121 10.182 1.00 29.00 B C ATOM 1018 O ASP B 46 69.178 −14.374 9.634 1.00 29.94 B O ATOM 1019 N THR B 47 69.768 −16.418 10.370 1.00 27.35 B N ATOM 1020 CA THR B 47 68.519 −17.036 9.961 1.00 25.63 B C ATOM 1021 CB THR B 47 68.686 −17.806 8.641 1.00 25.07 B C ATOM 1022 OG1 THR B 47 69.360 −19.038 8.886 1.00 28.76 B O ATOM 1023 CG2 THR B 47 69.517 −16.990 7.661 1.00 24.39 B C ATOM 1024 C THR B 47 68.045 −17.964 11.085 1.00 25.43 B C ATOM 1025 O THR B 47 68.833 −18.722 11.666 1.00 23.76 B O ATOM 1026 N TYR B 48 66.754 −17.873 11.401 1.00 24.10 B N ATOM 1027 CA TYR B 48 66.151 −18.659 12.469 1.00 21.15 B C ATOM 1028 CB TYR B 48 65.873 −17.779 13.689 1.00 17.82 B C ATOM 1029 CG TYR B 48 67.053 −16.997 14.195 1.00 16.59 B C ATOM 1030 CD1 TYR B 48 67.538 −15.899 13.490 1.00 13.77 B C ATOM 1031 CE1 TYR B 48 68.644 −15.183 13.950 1.00 14.25 B C ATOM 1032 CD2 TYR B 48 67.700 −17.367 15.381 1.00 15.66 B C ATOM 1033 CE2 TYR B 48 68.805 −16.660 15.849 1.00 13.98 B C ATOM 1034 CZ TYR B 48 69.273 −15.572 15.127 1.00 13.39 B C ATOM 1035 OH TYR B 48 70.378 −14.889 15.568 1.00 10.72 B O ATOM 1036 C TYR B 48 64.826 −19.249 12.054 1.00 21.47 B C ATOM 1037 O TYR B 48 64.346 −19.036 10.942 1.00 23.23 B O ATOM 1038 N THR B 49 64.241 −20.002 12.973 1.00 20.15 B N ATOM 1039 CA THR B 49 62.928 −20.572 12.767 1.00 19.98 B C ATOM 1040 CB THR B 49 62.837 −22.014 13.271 1.00 20.11 B C ATOM 1041 OG1 THR B 49 63.281 −22.072 14.632 1.00 19.72 B O ATOM 1042 CG2 THR B 49 63.692 −22.930 12.409 1.00 19.53 B C ATOM 1043 C THR B 49 62.101 −19.676 13.672 1.00 20.66 B C ATOM 1044 O THR B 49 62.632 −19.088 14.615 1.00 20.05 B O ATOM 1045 N MET B 50 60.815 −19.547 13.398 1.00 21.09 B N ATOM 1046 CA MET B 50 60.002 −18.694 14.238 1.00 21.27 B C ATOM 1047 CB MET B 50 58.545 −18.751 13.793 1.00 20.61 B C ATOM 1048 CG MET B 50 58.283 −18.012 12.491 1.00 19.47 B C ATOM 1049 SD MET B 50 58.635 −16.258 12.644 1.00 16.90 B S ATOM 1050 CE MET B 50 57.164 −15.708 13.480 1.00 18.57 B C ATOM 1051 C MET B 50 60.136 −19.095 15.700 1.00 22.23 B C ATOM 1052 O MET B 50 60.289 −18.239 16.571 1.00 23.85 B O ATOM 1053 N LYS B 51 60.105 −20.396 15.963 1.00 22.72 B N ATOM 1054 CA LYS B 51 60.212 −20.909 17.320 1.00 22.74 B C ATOM 1055 CB LYS B 51 60.233 −22.430 17.274 1.00 26.32 B C ATOM 1056 CG LYS B 51 60.382 −23.134 18.616 1.00 32.36 B C ATOM 1057 CD LYS B 51 60.556 −24.639 18.372 1.00 36.67 B C ATOM 1058 CE LYS B 51 60.845 −25.426 19.641 1.00 39.04 B C ATOM 1059 NZ LYS B 51 61.087 −26.867 19.327 1.00 39.73 B N ATOM 1060 C LYS B 51 61.449 −20.382 18.051 1.00 21.96 B C ATOM 1061 O LYS B 51 61.395 −20.092 19.247 1.00 20.43 B O ATOM 1062 N GLU B 52 62.559 −20.247 17.331 1.00 21.19 B N ATOM 1063 CA GLU B 52 63.792 −19.760 17.939 1.00 21.35 B C ATOM 1064 CB GLU B 52 64.999 −20.066 17.052 1.00 21.21 B C ATOM 1065 CG GLU B 52 65.197 −21.531 16.758 1.00 22.21 B C ATOM 1066 CD GLU B 52 66.345 −21.763 15.807 1.00 23.97 B C ATOM 1067 OE1 GLU B 52 66.385 −21.063 14.777 1.00 25.44 B O ATOM 1068 OE2 GLU B 52 67.200 −22.636 16.078 1.00 23.65 B O ATOM 1069 C GLU B 52 63.725 −18.266 18.178 1.00 21.58 B C ATOM 1070 O GLU B 52 64.227 −17.779 19.186 1.00 23.46 B O ATOM 1071 N VAL B 53 63.128 −17.534 17.242 1.00 21.11 B N ATOM 1072 CA VAL B 53 63.004 −16.092 17.398 1.00 19.95 B C ATOM 1073 CB VAL B 53 62.326 −15.433 16.172 1.00 19.49 B C ATOM 1074 CG1 VAL B 53 62.038 −13.960 16.454 1.00 19.40 B C ATOM 1075 CG2 VAL B 53 63.238 −15.544 14.965 1.00 16.87 B C ATOM 1076 C VAL B 53 62.175 −15.830 18.645 1.00 19.80 B C ATOM 1077 O VAL B 53 62.524 −14.980 19.466 1.00 20.88 B O ATOM 1078 N LEU B 54 61.085 −16.574 18.795 1.00 17.79 B N ATOM 1079 CA LEU B 54 60.230 −16.418 19.962 1.00 17.35 B C ATOM 1080 CB LEU B 54 59.030 −17.367 19.875 1.00 15.34 B C ATOM 1081 CG LEU B 54 57.869 −16.841 19.028 1.00 15.35 B C ATOM 1082 CD1 LEU B 54 56.934 −17.970 18.671 1.00 16.18 B C ATOM 1083 CD2 LEU B 54 57.139 −15.747 19.795 1.00 14.28 B C ATOM 1084 C LEU B 54 61.013 −16.697 21.232 1.00 18.28 B C ATOM 1085 O LEU B 54 60.891 −15.980 22.223 1.00 20.27 B O ATOM 1086 N PHE B 55 61.833 −17.739 21.202 1.00 17.82 B N ATOM 1087 CA PHE B 55 62.609 −18.092 22.379 1.00 16.45 B C ATOM 1088 CB PHE B 55 63.428 −19.360 22.137 1.00 15.18 B C ATOM 1089 CG PHE B 55 64.192 −19.814 23.342 1.00 12.26 B C ATOM 1090 CD1 PHE B 55 63.609 −20.666 24.267 1.00 12.57 B C ATOM 1091 CD2 PHE B 55 65.485 −19.366 23.566 1.00 12.20 B C ATOM 1092 CE1 PHE B 55 64.307 −21.071 25.406 1.00 13.48 B C ATOM 1093 CE2 PHE B 55 66.190 −19.761 24.699 1.00 14.43 B C ATOM 1094 CZ PHE B 55 65.600 −20.618 25.621 1.00 13.25 B C ATOM 1095 C PHE B 55 63.544 −16.970 22.803 1.00 15.94 B C ATOM 1096 O PHE B 55 63.599 −16.625 23.983 1.00 15.63 B O ATOM 1097 N TYR B 56 64.297 −16.419 21.854 1.00 14.98 B N ATOM 1098 CA TYR B 56 65.223 −15.338 22.179 1.00 15.81 B C ATOM 1099 CB TYR B 56 66.132 −15.033 20.989 1.00 13.78 B C ATOM 1100 CG TYR B 56 67.202 −16.080 20.787 1.00 14.13 B C ATOM 1101 CD1 TYR B 56 68.193 −16.285 21.752 1.00 12.86 B C ATOM 1102 CE1 TYR B 56 69.174 −17.252 21.576 1.00 12.44 B C ATOM 1103 CD2 TYR B 56 67.222 −16.876 19.638 1.00 12.17 B C ATOM 1104 CE2 TYR B 56 68.199 −17.845 19.450 1.00 10.79 B C ATOM 1105 CZ TYR B 56 69.171 −18.029 20.422 1.00 13.93 B C ATOM 1106 OH TYR B 56 70.143 −18.991 20.244 1.00 16.24 B O ATOM 1107 C TYR B 56 64.440 −14.100 22.577 1.00 16.28 B C ATOM 1108 O TYR B 56 64.821 −13.365 23.497 1.00 17.43 B O ATOM 1109 N LEU B 57 63.325 −13.885 21.895 1.00 15.05 B N ATOM 1110 CA LEU B 57 62.491 −12.742 22.191 1.00 14.33 B C ATOM 1111 CB LEU B 57 61.367 −12.654 21.161 1.00 9.51 B C ATOM 1112 CG LEU B 57 61.124 −11.303 20.489 1.00 7.58 B C ATOM 1113 CD1 LEU B 57 62.331 −10.388 20.577 1.00 3.80 B C ATOM 1114 CD2 LEU B 57 60.759 −11.572 19.048 1.00 8.90 B C ATOM 1115 C LEU B 57 61.954 −12.930 23.610 1.00 16.47 B C ATOM 1116 O LEU B 57 61.731 −11.953 24.342 1.00 18.25 B O ATOM 1117 N GLY B 58 61.772 −14.191 24.004 1.00 15.84 B N ATOM 1118 CA GLY B 58 61.295 −14.487 25.342 1.00 15.86 B C ATOM 1119 C GLY B 58 62.346 −14.152 26.381 1.00 16.79 B C ATOM 1120 O GLY B 58 62.017 −13.688 27.469 1.00 17.27 B O ATOM 1121 N GLN B 59 63.614 −14.387 26.048 1.00 18.11 B N ATOM 1122 CA GLN B 59 64.709 −14.095 26.969 1.00 19.44 B C ATOM 1123 CB GLN B 59 66.039 −14.681 26.476 1.00 20.58 B C ATOM 1124 CG GLN B 59 66.110 −16.200 26.415 1.00 21.38 B C ATOM 1125 CD GLN B 59 65.858 −16.858 27.753 1.00 21.66 B C ATOM 1126 OE1 GLN B 59 66.530 −16.563 28.737 1.00 22.01 B O ATOM 1127 NE2 GLN B 59 64.886 −17.765 27.794 1.00 21.89 B N ATOM 1128 C GLN B 59 64.847 −12.591 27.065 1.00 19.91 B C ATOM 1129 O GLN B 59 65.081 −12.049 28.147 1.00 20.54 B O ATOM 1130 N TYR B 60 64.712 −11.918 25.925 1.00 19.05 B N ATOM 1131 CA TYR B 60 64.810 −10.465 25.896 1.00 19.04 B C ATOM 1132 CB TYR B 60 64.539 −9.952 24.489 1.00 19.56 B C ATOM 1133 CG TYR B 60 64.745 −8.469 24.334 1.00 20.31 B C ATOM 1134 CD1 TYR B 60 65.989 −7.955 23.976 1.00 21.40 B C ATOM 1135 CE1 TYR B 60 66.183 −6.587 23.812 1.00 21.70 B C ATOM 1136 CD2 TYR B 60 63.694 −7.575 24.535 1.00 20.38 B C ATOM 1137 CE2 TYR B 60 63.872 −6.205 24.380 1.00 21.82 B C ATOM 1138 CZ TYR B 60 65.120 −5.714 24.014 1.00 22.80 B C ATOM 1139 OH TYR B 60 65.303 −4.360 23.827 1.00 20.51 B O ATOM 1140 C TYR B 60 63.779 −9.866 26.861 1.00 19.98 B C ATOM 1141 O TYR B 60 64.126 −9.128 27.791 1.00 18.48 B O ATOM 1142 N ILE B 61 62.507 −10.192 26.631 1.00 19.27 B N ATOM 1143 CA ILE B 61 61.425 −9.691 27.471 1.00 18.48 B C ATOM 1144 CB ILE B 61 60.093 −10.407 27.146 1.00 15.73 B C ATOM 1145 CG2 ILE B 61 59.081 −10.185 28.269 1.00 10.18 B C ATOM 1146 CG1 ILE B 61 59.562 −9.922 25.797 1.00 11.81 B C ATOM 1147 CD1 ILE B 61 58.345 −10.669 25.332 1.00 8.80 B C ATOM 1148 C ILE B 61 61.744 −9.913 28.943 1.00 20.88 B C ATOM 1149 O ILE B 61 61.638 −9.002 29.763 1.00 19.97 B O ATOM 1150 N MET B 62 62.152 −11.132 29.265 1.00 23.54 B N ATOM 1151 CA MET B 62 62.448 −11.486 30.640 1.00 25.72 B C ATOM 1152 CB MET B 62 62.643 −12.993 30.753 1.00 26.08 B C ATOM 1153 CG MET B 62 62.091 −13.549 32.035 1.00 29.56 B C ATOM 1154 SD MET B 62 60.293 −13.384 32.054 1.00 34.09 B S ATOM 1155 CE MET B 62 59.820 −15.029 31.546 1.00 35.99 B C ATOM 1156 C MET B 62 63.668 −10.773 31.202 1.00 26.75 B C ATOM 1157 O MET B 62 63.642 −10.272 32.331 1.00 25.96 B O ATOM 1158 N THR B 63 64.735 −10.728 30.413 1.00 27.94 B N ATOM 1159 CA THR B 63 65.970 −10.101 30.853 1.00 29.87 B C ATOM 1160 CB THR B 63 67.103 −10.310 29.814 1.00 30.48 B C ATOM 1161 OG1 THR B 63 68.312 −9.735 30.311 1.00 33.04 B O ATOM 1162 CG2 THR B 63 66.773 −9.641 28.499 1.00 32.87 B C ATOM 1163 C THR B 63 65.814 −8.610 31.155 1.00 30.83 B C ATOM 1164 O THR B 63 66.369 −8.113 32.140 1.00 30.48 B O ATOM 1165 N LYS B 64 65.053 −7.900 30.321 1.00 31.66 B N ATOM 1166 CA LYS B 64 64.837 −6.470 30.522 1.00 31.45 B C ATOM 1167 CB LYS B 64 64.707 −5.759 29.174 1.00 30.49 B C ATOM 1168 CG LYS B 64 65.875 −6.026 28.246 1.00 30.78 B C ATOM 1169 CD LYS B 64 65.886 −5.111 27.038 1.00 27.93 B C ATOM 1170 CE LYS B 64 66.248 −3.691 27.430 1.00 28.58 B C ATOM 1171 NZ LYS B 64 66.497 −2.836 26.235 1.00 28.06 B N ATOM 1172 C LYS B 64 63.608 −6.182 31.386 1.00 32.45 B C ATOM 1173 O LYS B 64 63.177 −5.039 31.502 1.00 33.33 B O ATOM 1174 N ARG B 65 63.049 −7.222 31.993 1.00 33.64 B N ATOM 1175 CA ARG B 65 61.888 −7.067 32.861 1.00 34.41 B C ATOM 1176 CB ARG B 65 62.332 −6.516 34.215 1.00 36.81 B C ATOM 1177 CG ARG B 65 63.229 −7.457 34.994 1.00 41.86 B C ATOM 1178 CD ARG B 65 63.308 −7.042 36.452 1.00 47.34 B C ATOM 1179 NE ARG B 65 63.686 −8.162 37.311 1.00 52.97 B N ATOM 1180 CZ ARG B 65 63.593 −8.153 38.640 1.00 55.54 B C ATOM 1181 NH1 ARG B 65 63.132 −7.076 39.269 1.00 56.75 B N ATOM 1182 NH2 ARG B 65 63.954 −9.225 39.340 1.00 55.33 B N ATOM 1183 C ARG B 65 60.826 −6.153 32.265 1.00 32.74 B C ATOM 1184 O ARG B 65 60.469 −5.140 32.862 1.00 32.38 B O ATOM 1185 N LEU B 66 60.317 −6.523 31.093 1.00 31.30 B N ATOM 1186 CA LEU B 66 59.304 −5.730 30.402 1.00 28.77 B C ATOM 1187 CB LEU B 66 59.529 −5.786 28.885 1.00 27.49 B C ATOM 1188 CG LEU B 66 60.893 −5.336 28.347 1.00 26.11 B C ATOM 1189 CD1 LEU B 66 60.878 −5.401 26.831 1.00 24.34 B C ATOM 1190 CD2 LEU B 66 61.211 −3.920 28.820 1.00 23.56 B C ATOM 1191 C LEU B 66 57.884 −6.176 30.709 1.00 27.69 B C ATOM 1192 O LEU B 66 56.928 −5.585 30.217 1.00 27.56 B O ATOM 1193 N TYR B 67 57.741 −7.212 31.523 1.00 27.33 B N ATOM 1194 CA TYR B 67 56.415 −7.708 31.854 1.00 29.61 B C ATOM 1195 CB TYR B 67 56.498 −9.181 32.248 1.00 29.82 B C ATOM 1196 CG TYR B 67 57.457 −9.436 33.379 1.00 31.91 B C ATOM 1197 CD1 TYR B 67 57.097 −9.158 34.696 1.00 31.85 B C ATOM 1198 CE1 TYR B 67 58.000 −9.322 35.735 1.00 34.03 B C ATOM 1199 CD2 TYR B 67 58.749 −9.895 33.129 1.00 33.25 B C ATOM 1200 CE2 TYR B 67 59.664 −10.063 34.165 1.00 34.17 B C ATOM 1201 CZ TYR B 67 59.282 −9.770 35.463 1.00 35.02 B C ATOM 1202 OH TYR B 67 60.190 −9.884 36.488 1.00 37.50 B O ATOM 1203 C TYR B 67 55.785 −6.890 32.974 1.00 31.35 B C ATOM 1204 O TYR B 67 56.481 −6.367 33.842 1.00 30.58 B O ATOM 1205 N ASP B 68 54.461 −6.775 32.940 1.00 33.62 B N ATOM 1206 CA ASP B 68 53.721 −6.020 33.944 1.00 35.75 B C ATOM 1207 CB ASP B 68 52.294 −5.755 33.457 1.00 36.70 B C ATOM 1208 CG ASP B 68 51.532 −4.804 34.366 1.00 37.77 B C ATOM 1209 OD1 ASP B 68 51.592 −4.975 35.606 1.00 36.47 B O ATOM 1210 OD2 ASP B 68 50.865 −3.888 33.831 1.00 39.59 B O ATOM 1211 C ASP B 68 53.675 −6.795 35.254 1.00 37.04 B C ATOM 1212 O ASP B 68 53.107 −7.885 35.319 1.00 35.87 B O ATOM 1213 N GLU B 69 54.262 −6.221 36.298 1.00 39.00 B N ATOM 1214 CA GLU B 69 54.293 −6.871 37.601 1.00 42.69 B C ATOM 1215 CB GLU B 69 54.897 −5.931 38.649 1.00 46.78 B C ATOM 1216 CG GLU B 69 56.421 −5.965 38.713 1.00 52.39 B C ATOM 1217 CD GLU B 69 56.957 −7.259 39.318 1.00 55.48 B C ATOM 1218 OE1 GLU B 69 56.779 −7.472 40.541 1.00 56.57 B O ATOM 1219 OE2 GLU B 69 57.552 −8.063 38.566 1.00 56.69 B O ATOM 1220 C GLU B 69 52.945 −7.379 38.098 1.00 42.30 B C ATOM 1221 O GLU B 69 52.866 −8.467 38.667 1.00 42.32 B O ATOM 1222 N LYS B 70 51.884 −6.608 37.888 1.00 42.26 B N ATOM 1223 CA LYS B 70 50.571 −7.031 38.362 1.00 42.71 B C ATOM 1224 CB LYS B 70 49.920 −5.908 39.174 1.00 44.44 B C ATOM 1225 CG LYS B 70 50.148 −4.517 38.629 1.00 46.51 B C ATOM 1226 CD LYS B 70 49.718 −3.481 39.651 1.00 48.94 B C ATOM 1227 CE LYS B 70 50.071 −2.075 39.199 1.00 50.32 B C ATOM 1228 NZ LYS B 70 49.862 −1.093 40.295 1.00 50.28 B N ATOM 1229 C LYS B 70 49.623 −7.529 37.281 1.00 41.71 B C ATOM 1230 O LYS B 70 48.455 −7.808 37.541 1.00 41.35 B O ATOM 1231 N GLN B 71 50.139 −7.645 36.066 1.00 41.60 B N ATOM 1232 CA GLN B 71 49.370 −8.142 34.933 1.00 40.95 B C ATOM 1233 CB GLN B 71 48.677 −6.996 34.204 1.00 42.04 B C ATOM 1234 CG GLN B 71 47.439 −7.421 33.445 1.00 45.02 B C ATOM 1235 CD GLN B 71 46.287 −7.799 34.365 1.00 47.37 B C ATOM 1236 OE1 GLN B 71 45.234 −8.260 33.908 1.00 48.26 B O ATOM 1237 NE2 GLN B 71 46.477 −7.599 35.667 1.00 47.17 B N ATOM 1238 C GLN B 71 50.452 −8.753 34.065 1.00 40.06 B C ATOM 1239 O GLN B 71 50.741 −8.283 32.971 1.00 40.40 B O ATOM 1240 N GLN B 72 51.055 −9.809 34.593 1.00 39.58 B N ATOM 1241 CA GLN B 72 52.156 −10.493 33.944 1.00 38.53 B C ATOM 1242 CB GLN B 72 52.618 −11.645 34.838 1.00 39.47 B C ATOM 1243 CG GLN B 72 53.533 −11.159 35.958 1.00 42.58 B C ATOM 1244 CD GLN B 72 53.760 −12.189 37.045 1.00 44.14 B C ATOM 1245 OE1 GLN B 72 53.965 −13.374 36.768 1.00 44.60 B O ATOM 1246 NE2 GLN B 72 53.740 −11.737 38.294 1.00 44.27 B N ATOM 1247 C GLN B 72 51.988 −10.958 32.508 1.00 36.28 B C ATOM 1248 O GLN B 72 52.984 −11.181 31.824 1.00 36.90 B O ATOM 1249 N HIS B 73 50.753 −11.090 32.036 1.00 33.40 B N ATOM 1250 CA HIS B 73 50.532 −11.520 30.655 1.00 31.29 B C ATOM 1251 CB HIS B 73 49.138 −12.134 30.519 1.00 32.90 B C ATOM 1252 CG HIS B 73 48.030 −11.173 30.794 1.00 36.49 B C ATOM 1253 CD2 HIS B 73 47.521 −10.711 31.962 1.00 36.77 B C ATOM 1254 ND1 HIS B 73 47.339 −10.527 29.790 1.00 38.38 B N ATOM 1255 CE1 HIS B 73 46.454 −9.706 30.328 1.00 39.39 B C ATOM 1256 NE2 HIS B 73 46.545 −9.799 31.644 1.00 39.50 B N ATOM 1257 C HIS B 73 50.705 −10.359 29.659 1.00 28.64 B C ATOM 1258 O HIS B 73 50.638 −10.550 28.444 1.00 25.66 B O ATOM 1259 N ILE B 74 50.945 −9.163 30.196 1.00 27.08 B N ATOM 1260 CA ILE B 74 51.131 −7.953 29.398 1.00 25.27 B C ATOM 1261 CB ILE B 74 50.359 −6.751 29.989 1.00 24.67 B C ATOM 1262 CG2 ILE B 74 50.705 −5.491 29.219 1.00 23.79 B C ATOM 1263 CG1 ILE B 74 48.854 −7.010 29.951 1.00 24.80 B C ATOM 1264 CD1 ILE B 74 48.032 −5.855 30.499 1.00 24.32 B C ATOM 1265 C ILE B 74 52.596 −7.535 29.322 1.00 24.48 B C ATOM 1266 O ILE B 74 53.253 −7.348 30.347 1.00 25.75 B O ATOM 1267 N VAL B 75 53.104 −7.387 28.106 1.00 22.76 B N ATOM 1268 CA VAL B 75 54.479 −6.961 27.914 1.00 21.41 B C ATOM 1269 CB VAL B 75 55.142 −7.727 26.751 1.00 20.53 B C ATOM 1270 CG1 VAL B 75 56.484 −7.089 26.387 1.00 16.35 B C ATOM 1271 CG2 VAL B 75 55.339 −9.184 27.154 1.00 18.41 B C ATOM 1272 C VAL B 75 54.441 −5.470 27.607 1.00 22.75 B C ATOM 1273 O VAL B 75 54.003 −5.053 26.535 1.00 23.83 B O ATOM 1274 N TYR B 76 54.871 −4.662 28.568 1.00 23.61 B N ATOM 1275 CA TYR B 76 54.880 −3.218 28.382 1.00 23.27 B C ATOM 1276 CB TYR B 76 54.705 −2.508 29.730 1.00 22.31 B C ATOM 1277 CG TYR B 76 54.327 −1.065 29.569 1.00 22.16 B C ATOM 1278 CD1 TYR B 76 53.049 −0.703 29.142 1.00 22.65 B C ATOM 1279 CE1 TYR B 76 52.725 0.621 28.879 1.00 23.30 B C ATOM 1280 CD2 TYR B 76 55.274 −0.064 29.739 1.00 23.08 B C ATOM 1281 CE2 TYR B 76 54.968 1.264 29.477 1.00 26.22 B C ATOM 1282 CZ TYR B 76 53.694 1.602 29.044 1.00 26.37 B C ATOM 1283 OH TYR B 76 53.422 2.917 28.750 1.00 27.15 B O ATOM 1284 C TYR B 76 56.212 −2.842 27.733 1.00 22.74 B C ATOM 1285 O TYR B 76 57.232 −2.714 28.408 1.00 23.63 B O ATOM 1286 N CYS B 77 56.195 −2.675 26.416 1.00 21.72 B N ATOM 1287 CA CYS B 77 57.404 −2.361 25.668 1.00 22.93 B C ATOM 1288 CB CYS B 77 57.533 −3.317 24.482 1.00 22.60 B C ATOM 1289 SG CYS B 77 56.064 −3.392 23.417 1.00 22.36 B S ATOM 1290 C CYS B 77 57.434 −0.937 25.155 1.00 23.94 B C ATOM 1291 O CYS B 77 58.189 −0.612 24.240 1.00 22.38 B O ATOM 1292 N SER B 78 56.624 −0.084 25.763 1.00 26.48 B N ATOM 1293 CA SER B 78 56.530 1.303 25.336 1.00 28.51 B C ATOM 1294 CB SER B 78 55.592 2.067 26.267 1.00 29.24 B C ATOM 1295 OG SER B 78 55.163 3.260 25.642 1.00 31.92 B O ATOM 1296 C SER B 78 57.857 2.050 25.221 1.00 29.04 B C ATOM 1297 O SER B 78 58.106 2.703 24.213 1.00 28.79 B O ATOM 1298 N ASN B 79 58.710 1.955 26.239 1.00 29.62 B N ATOM 1299 CA ASN B 79 59.988 2.668 26.207 1.00 30.17 B C ATOM 1300 CB ASN B 79 60.224 3.383 27.538 1.00 32.72 B C ATOM 1301 CG ASN B 79 58.954 3.952 28.121 1.00 35.50 B C ATOM 1302 OD1 ASN B 79 58.350 3.352 29.013 1.00 38.27 B O ATOM 1303 ND2 ASN B 79 58.525 5.104 27.609 1.00 34.49 B N ATOM 1304 C ASN B 79 61.176 1.768 25.911 1.00 29.56 B C ATOM 1305 O ASN B 79 62.276 1.996 26.407 1.00 29.57 B O ATOM 1306 N ASP B 80 60.955 0.750 25.092 1.00 28.47 B N ATOM 1307 CA ASP B 80 62.008 −0.185 24.746 1.00 26.85 B C ATOM 1308 CB ASP B 80 61.680 −1.556 25.348 1.00 26.05 B C ATOM 1309 CG ASP B 80 62.854 −2.511 25.311 1.00 25.69 B C ATOM 1310 OD1 ASP B 80 63.632 −2.521 26.284 1.00 25.43 B O ATOM 1311 OD2 ASP B 80 63.004 −3.243 24.307 1.00 26.27 B O ATOM 1312 C ASP B 80 62.058 −0.281 23.229 1.00 26.74 B C ATOM 1313 O ASP B 80 61.064 0.002 22.560 1.00 26.42 B O ATOM 1314 N LEU B 81 63.205 −0.673 22.680 1.00 27.17 B N ATOM 1315 CA LEU B 81 63.319 −0.811 21.229 1.00 26.44 B C ATOM 1316 CB LEU B 81 64.707 −1.331 20.832 1.00 26.94 B C ATOM 1317 CG LEU B 81 64.835 −1.918 19.411 1.00 29.76 B C ATOM 1318 CD1 LEU B 81 64.428 −0.886 18.373 1.00 29.96 B C ATOM 1319 CD2 LEU B 81 66.264 −2.391 19.158 1.00 29.94 B C ATOM 1320 C LEU B 81 62.248 −1.786 20.748 1.00 25.72 B C ATOM 1321 O LEU B 81 61.798 −1.716 19.597 1.00 25.96 B O ATOM 1322 N LEU B 82 61.838 −2.695 21.632 1.00 23.41 B N ATOM 1323 CA LEU B 82 60.818 −3.670 21.268 1.00 21.59 B C ATOM 1324 CB LEU B 82 60.581 −4.659 22.403 1.00 19.12 B C ATOM 1325 CG LEU B 82 59.634 −5.806 22.035 1.00 17.58 B C ATOM 1326 CD1 LEU B 82 60.102 −6.468 20.739 1.00 14.71 B C ATOM 1327 CD2 LEU B 82 59.584 −6.799 23.174 1.00 12.80 B C ATOM 1328 C LEU B 82 59.521 −2.958 20.929 1.00 20.92 B C ATOM 1329 O LEU B 82 58.707 −3.463 20.156 1.00 21.23 B O ATOM 1330 N GLY B 83 59.343 −1.773 21.506 1.00 19.85 B N ATOM 1331 CA GLY B 83 58.149 −0.998 21.243 1.00 20.09 B C ATOM 1332 C GLY B 83 58.145 −0.476 19.823 1.00 19.56 B C ATOM 1333 O GLY B 83 57.116 −0.492 19.148 1.00 17.01 B O ATOM 1334 N ASP B 84 59.307 −0.024 19.366 1.00 21.15 B N ATOM 1335 CA ASP B 84 59.440 0.508 18.016 1.00 24.31 B C ATOM 1336 CB ASP B 84 60.818 1.172 17.841 1.00 25.48 B C ATOM 1337 CG ASP B 84 60.995 2.415 18.713 1.00 27.23 B C ATOM 1338 OD1 ASP B 84 60.111 3.297 18.665 1.00 26.20 B O ATOM 1339 OD2 ASP B 84 62.018 2.520 19.434 1.00 26.96 B O ATOM 1340 C ASP B 84 59.240 −0.561 16.935 1.00 25.88 B C ATOM 1341 O ASP B 84 58.595 −0.310 15.909 1.00 25.90 B O ATOM 1342 N LEU B 85 59.790 −1.753 17.164 1.00 27.13 B N ATOM 1343 CA LEU B 85 59.677 −2.837 16.189 1.00 27.46 B C ATOM 1344 CB LEU B 85 60.688 −3.948 16.504 1.00 30.69 B C ATOM 1345 CG LEU B 85 62.168 −3.543 16.434 1.00 34.05 B C ATOM 1346 CD1 LEU B 85 63.041 −4.711 16.850 1.00 34.94 B C ATOM 1347 CD2 LEU B 85 62.523 −3.097 15.020 1.00 34.47 B C ATOM 1348 C LEU B 85 58.275 −3.426 16.105 1.00 26.06 B C ATOM 1349 O LEU B 85 57.812 −3.771 15.018 1.00 25.20 B O ATOM 1350 N PHE B 86 57.600 −3.545 17.248 1.00 24.87 B N ATOM 1351 CA PHE B 86 56.246 −4.099 17.272 1.00 23.58 B C ATOM 1352 CB PHE B 86 55.992 −4.819 18.602 1.00 21.60 B C ATOM 1353 CG PHE B 86 56.485 −6.245 18.634 1.00 20.28 B C ATOM 1354 CD1 PHE B 86 57.418 −6.704 17.705 1.00 18.78 B C ATOM 1355 CD2 PHE B 86 56.018 −7.129 19.612 1.00 19.50 B C ATOM 1356 CE1 PHE B 86 57.877 −8.015 17.749 1.00 19.74 B C ATOM 1357 CE2 PHE B 86 56.470 −8.449 19.671 1.00 17.87 B C ATOM 1358 CZ PHE B 86 57.400 −8.896 18.739 1.00 20.02 B C ATOM 1359 C PHE B 86 55.170 −3.036 17.029 1.00 23.30 B C ATOM 1360 O PHE B 86 54.005 −3.358 16.789 1.00 23.27 B O ATOM 1361 N GLY B 87 55.566 −1.770 17.097 1.00 22.81 B N ATOM 1362 CA GLY B 87 54.632 −0.684 16.854 1.00 23.05 B C ATOM 1363 C GLY B 87 53.544 −0.487 17.889 1.00 22.49 B C ATOM 1364 O GLY B 87 52.536 0.171 17.626 1.00 23.12 B O ATOM 1365 N VAL B 88 53.737 −1.054 19.069 1.00 21.70 B N ATOM 1366 CA VAL B 88 52.752 −0.905 20.125 1.00 20.61 B C ATOM 1367 CB VAL B 88 51.906 −2.186 20.282 1.00 21.23 B C ATOM 1368 CG1 VAL B 88 51.039 −2.373 19.045 1.00 19.66 B C ATOM 1369 CG2 VAL B 88 52.806 −3.398 20.503 1.00 18.17 B C ATOM 1370 C VAL B 88 53.375 −0.552 21.465 1.00 19.81 B C ATOM 1371 O VAL B 88 54.529 −0.873 21.745 1.00 21.01 B O ATOM 1372 N PRO B 89 52.624 0.149 22.309 1.00 18.83 B N ATOM 1373 CD PRO B 89 51.277 0.723 22.155 1.00 18.07 B C ATOM 1374 CA PRO B 89 53.197 0.494 23.604 1.00 18.34 B C ATOM 1375 CB PRO B 89 52.271 1.605 24.083 1.00 17.37 B C ATOM 1376 CG PRO B 89 50.948 1.154 23.568 1.00 16.24 B C ATOM 1377 C PRO B 89 53.168 −0.759 24.504 1.00 18.24 B C ATOM 1378 O PRO B 89 53.833 −0.823 25.544 1.00 18.86 B O ATOM 1379 N SER B 90 52.399 −1.760 24.087 1.00 16.38 B N ATOM 1380 CA SER B 90 52.290 −2.989 24.855 1.00 16.34 B C ATOM 1381 CB SER B 90 51.553 −2.723 26.170 1.00 15.92 B C ATOM 1382 OG SER B 90 50.163 −2.503 25.954 1.00 13.70 B O ATOM 1383 C SER B 90 51.529 −4.038 24.058 1.00 17.83 B C ATOM 1384 O SER B 90 50.968 −3.737 22.998 1.00 19.24 B O ATOM 1385 N PHE B 91 51.516 −5.268 24.568 1.00 17.29 B N ATOM 1386 CA PHE B 91 50.799 −6.365 23.922 1.00 18.18 B C ATOM 1387 CB PHE B 91 51.543 −6.839 22.653 1.00 19.29 B C ATOM 1388 CG PHE B 91 52.875 −7.496 22.918 1.00 18.47 B C ATOM 1389 CD1 PHE B 91 52.946 −8.818 23.347 1.00 19.20 B C ATOM 1390 CD2 PHE B 91 54.058 −6.788 22.746 1.00 18.75 B C ATOM 1391 CE1 PHE B 91 54.180 −9.425 23.603 1.00 18.97 B C ATOM 1392 CE2 PHE B 91 55.298 −7.384 23.000 1.00 18.74 B C ATOM 1393 CZ PHE B 91 55.358 −8.702 23.429 1.00 18.69 B C ATOM 1394 C PHE B 91 50.638 −7.504 24.911 1.00 17.40 B C ATOM 1395 O PHE B 91 51.350 −7.565 25.899 1.00 17.57 B O ATOM 1396 N SER B 92 49.693 −8.397 24.652 1.00 19.56 B N ATOM 1397 CA SER B 92 49.454 −9.539 25.536 1.00 21.79 B C ATOM 1398 CB SER B 92 47.942 −9.736 25.737 1.00 21.20 B C ATOM 1399 OG SER B 92 47.662 −10.770 26.676 1.00 21.59 B O ATOM 1400 C SER B 92 50.075 −10.820 24.952 1.00 22.70 B C ATOM 1401 O SER B 92 49.967 −11.074 23.748 1.00 22.64 B O ATOM 1402 N VAL B 93 50.722 −11.626 25.795 1.00 23.39 B N ATOM 1403 CA VAL B 93 51.332 −12.866 25.318 1.00 23.01 B C ATOM 1404 CB VAL B 93 52.384 −13.398 26.293 1.00 21.98 B C ATOM 1405 CG1 VAL B 93 53.500 −12.374 26.422 1.00 20.97 B C ATOM 1406 CG2 VAL B 93 51.743 −13.724 27.649 1.00 20.03 B C ATOM 1407 C VAL B 93 50.294 −13.951 25.071 1.00 23.92 B C ATOM 1408 O VAL B 93 50.627 −15.108 24.845 1.00 24.02 B O ATOM 1409 N LYS B 94 49.029 −13.562 25.116 1.00 25.51 B N ATOM 1410 CA LYS B 94 47.938 −14.486 24.857 1.00 26.63 B C ATOM 1411 CB LYS B 94 46.795 −14.228 25.835 1.00 27.11 B C ATOM 1412 CG LYS B 94 47.160 −14.514 27.278 1.00 28.58 B C ATOM 1413 CD LYS B 94 45.969 −14.285 28.187 1.00 30.27 B C ATOM 1414 CE LYS B 94 46.280 −14.710 29.607 1.00 33.38 B C ATOM 1415 NZ LYS B 94 45.116 −14.468 30.507 1.00 34.90 B N ATOM 1416 C LYS B 94 47.469 −14.286 23.410 1.00 26.79 B C ATOM 1417 O LYS B 94 46.834 −15.162 22.824 1.00 26.60 B O ATOM 1418 N GLU B 95 47.800 −13.125 22.848 1.00 27.48 B N ATOM 1419 CA GLU B 95 47.457 −12.777 21.469 1.00 28.49 B C ATOM 1420 CB GLU B 95 47.538 −11.265 21.265 1.00 30.15 B C ATOM 1421 CG GLU B 95 46.813 −10.455 22.298 1.00 34.01 B C ATOM 1422 CD GLU B 95 45.337 −10.472 22.077 1.00 35.09 B C ATOM 1423 OE1 GLU B 95 44.876 −9.780 21.143 1.00 36.48 B O ATOM 1424 OE2 GLU B 95 44.644 −11.187 22.829 1.00 37.63 B O ATOM 1425 C GLU B 95 48.520 −13.419 20.595 1.00 27.44 B C ATOM 1426 O GLU B 95 49.365 −12.723 20.043 1.00 28.88 B O ATOM 1427 N HIS B 96 48.486 −14.736 20.457 1.00 26.64 B N ATOM 1428 CA HIS B 96 49.510 −15.404 19.668 1.00 25.78 B C ATOM 1429 CB HIS B 96 49.359 −16.925 19.785 1.00 26.67 B C ATOM 1430 CG HIS B 96 49.608 −17.439 21.173 1.00 28.50 B C ATOM 1431 CD2 HIS B 96 49.587 −16.809 22.371 1.00 29.42 B C ATOM 1432 ND1 HIS B 96 49.939 −18.750 21.442 1.00 29.54 B N ATOM 1433 CE1 HIS B 96 50.115 −18.904 22.741 1.00 27.62 B C ATOM 1434 NE2 HIS B 96 49.907 −17.741 23.329 1.00 29.39 B N ATOM 1435 C HIS B 96 49.597 −14.968 18.215 1.00 24.28 B C ATOM 1436 O HIS B 96 50.686 −14.616 17.746 1.00 23.29 B O ATOM 1437 N ARG B 97 48.466 −14.956 17.510 1.00 22.65 B N ATOM 1438 CA ARG B 97 48.468 −14.558 16.106 1.00 21.17 B C ATOM 1439 CB ARG B 97 47.078 −14.744 15.489 1.00 20.89 B C ATOM 1440 CG ARG B 97 46.978 −14.295 14.033 1.00 20.94 B C ATOM 1441 CD ARG B 97 48.087 −14.896 13.193 1.00 20.01 B C ATOM 1442 NE ARG B 97 47.927 −16.334 13.019 1.00 21.31 B N ATOM 1443 CZ ARG B 97 48.882 −17.142 12.561 1.00 21.37 B C ATOM 1444 NH1 ARG B 97 50.071 −16.654 12.235 1.00 18.20 B N ATOM 1445 NH2 ARG B 97 48.645 −18.440 12.420 1.00 20.87 B N ATOM 1446 C ARG B 97 48.950 −13.125 15.904 1.00 20.86 B C ATOM 1447 O ARG B 97 49.616 −12.830 14.916 1.00 19.69 B O ATOM 1448 N LYS B 98 48.628 −12.232 16.837 1.00 21.99 B N ATOM 1449 CA LYS B 98 49.078 −10.841 16.718 1.00 23.04 B C ATOM 1450 CB LYS B 98 48.389 −9.940 17.756 1.00 26.28 B C ATOM 1451 CG LYS B 98 46.886 −9.739 17.532 1.00 31.67 B C ATOM 1452 CD LYS B 98 46.057 −10.965 17.958 1.00 35.98 B C ATOM 1453 CE LYS B 98 44.555 −10.651 17.958 1.00 36.14 B C ATOM 1454 NZ LYS B 98 43.773 −11.582 18.832 1.00 37.04 B N ATOM 1455 C LYS B 98 50.601 −10.737 16.876 1.00 20.53 B C ATOM 1456 O LYS B 98 51.261 −9.956 16.185 1.00 20.06 B O ATOM 1457 N ILE B 99 51.157 −11.526 17.789 1.00 18.42 B N ATOM 1458 CA ILE B 99 52.597 −11.520 18.001 1.00 15.84 B C ATOM 1459 CB ILE B 99 52.958 −12.351 19.241 1.00 13.76 B C ATOM 1460 CG2 ILE B 99 54.458 −12.421 19.410 1.00 11.35 B C ATOM 1461 CG1 ILE B 99 52.328 −11.694 20.472 1.00 11.87 B C ATOM 1462 CD1 ILE B 99 52.544 −12.440 21.748 1.00 12.22 B C ATOM 1463 C ILE B 99 53.308 −12.044 16.748 1.00 16.09 B C ATOM 1464 O ILE B 99 54.308 −11.475 16.312 1.00 15.12 B O ATOM 1465 N TYR B 100 52.784 −13.112 16.150 1.00 16.07 B N ATOM 1466 CA TYR B 100 53.388 −13.640 14.935 1.00 16.12 B C ATOM 1467 CB TYR B 100 52.638 −14.885 14.451 1.00 16.92 B C ATOM 1468 CG TYR B 100 53.290 −16.161 14.930 1.00 18.29 B C ATOM 1469 CD1 TYR B 100 53.464 −16.401 16.296 1.00 20.11 B C ATOM 1470 CE1 TYR B 100 54.145 −17.529 16.753 1.00 20.56 B C ATOM 1471 CD2 TYR B 100 53.806 −17.088 14.026 1.00 17.96 B C ATOM 1472 CE2 TYR B 100 54.492 −18.222 14.469 1.00 20.61 B C ATOM 1473 CZ TYR B 100 54.660 −18.434 15.839 1.00 21.77 B C ATOM 1474 OH TYR B 100 55.352 −19.532 16.302 1.00 21.77 B O ATOM 1475 C TYR B 100 53.398 −12.566 13.853 1.00 15.97 B C ATOM 1476 O TYR B 100 54.403 −12.368 13.157 1.00 15.84 B O ATOM 1477 N THR B 101 52.281 −11.857 13.728 1.00 15.24 B N ATOM 1478 CA THR B 101 52.178 −10.798 12.737 1.00 12.81 B C ATOM 1479 CB THR B 101 50.794 −10.162 12.755 1.00 10.68 B C ATOM 1480 OG1 THR B 101 49.832 −11.108 12.267 1.00 6.90 B O ATOM 1481 CG2 THR B 101 50.777 −8.914 11.897 1.00 8.15 B C ATOM 1482 C THR B 101 53.224 −9.727 12.994 1.00 14.35 B C ATOM 1483 O THR B 101 53.925 −9.305 12.076 1.00 14.48 B O ATOM 1484 N MET B 102 53.346 −9.289 14.241 1.00 15.04 B N ATOM 1485 CA MET B 102 54.335 −8.263 14.548 1.00 16.55 B C ATOM 1486 CB MET B 102 54.252 −7.858 16.020 1.00 17.06 B C ATOM 1487 CG MET B 102 52.938 −7.190 16.387 1.00 18.59 B C ATOM 1488 SD MET B 102 52.887 −6.559 18.084 1.00 20.90 B S ATOM 1489 CE MET B 102 52.530 −8.045 18.993 1.00 19.21 B C ATOM 1490 C MET B 102 55.752 −8.731 14.209 1.00 16.63 B C ATOM 1491 O MET B 102 56.572 −7.954 13.721 1.00 16.93 B O ATOM 1492 N ILE B 103 56.037 −10.005 14.452 1.00 16.66 B N ATOM 1493 CA ILE B 103 57.361 −10.538 14.166 1.00 15.88 B C ATOM 1494 CB ILE B 103 57.552 −11.920 14.824 1.00 14.19 B C ATOM 1495 CG2 ILE B 103 58.936 −12.470 14.497 1.00 13.58 B C ATOM 1496 CG1 ILE B 103 57.382 −11.789 16.338 1.00 12.02 B C ATOM 1497 CD1 ILE B 103 57.347 −13.103 17.063 1.00 10.93 B C ATOM 1498 C ILE B 103 57.606 −10.642 12.659 1.00 16.51 B C ATOM 1499 O ILE B 103 58.693 −10.308 12.176 1.00 14.91 B O ATOM 1500 N TYR B 104 56.586 −11.092 11.930 1.00 17.76 B N ATOM 1501 CA TYR B 104 56.656 −11.248 10.475 1.00 19.65 B C ATOM 1502 CB TYR B 104 55.316 −11.759 9.937 1.00 20.38 B C ATOM 1503 CG TYR B 104 55.101 −13.245 10.084 1.00 20.01 B C ATOM 1504 CD1 TYR B 104 53.824 −13.765 10.316 1.00 20.42 B C ATOM 1505 CE1 TYR B 104 53.611 −15.146 10.433 1.00 20.60 B C ATOM 1506 CD2 TYR B 104 56.168 −14.139 9.969 1.00 19.63 B C ATOM 1507 CE2 TYR B 104 55.968 −15.524 10.082 1.00 21.70 B C ATOM 1508 CZ TYR B 104 54.689 −16.016 10.313 1.00 21.03 B C ATOM 1509 OH TYR B 104 54.491 −17.369 10.414 1.00 22.28 B O ATOM 1510 C TYR B 104 57.020 −9.953 9.752 1.00 21.14 B C ATOM 1511 O TYR B 104 57.773 −9.972 8.774 1.00 21.46 B O ATOM 1512 N ARG B 105 56.473 −8.836 10.227 1.00 21.73 B N ATOM 1513 CA ARG B 105 56.750 −7.530 9.639 1.00 22.79 B C ATOM 1514 CB ARG B 105 55.918 −6.449 10.333 1.00 23.94 B C ATOM 1515 CG ARG B 105 54.422 −6.692 10.285 1.00 26.38 B C ATOM 1516 CD ARG B 105 53.657 −5.644 11.080 1.00 28.24 B C ATOM 1517 NE ARG B 105 53.572 −4.363 10.383 1.00 31.13 B N ATOM 1518 CZ ARG B 105 52.874 −3.320 10.824 1.00 32.03 B C ATOM 1519 NH1 ARG B 105 52.202 −3.404 11.966 1.00 33.02 B N ATOM 1520 NH2 ARG B 105 52.830 −2.200 10.116 1.00 31.61 B N ATOM 1521 C ARG B 105 58.234 −7.184 9.766 1.00 23.57 B C ATOM 1522 O ARG B 105 58.760 −6.377 8.999 1.00 22.90 B O ATOM 1523 N ASN B 106 58.905 −7.798 10.739 1.00 24.76 B N ATOM 1524 CA ASN B 106 60.327 −7.555 10.964 1.00 24.10 B C ATOM 1525 CB ASN B 106 60.642 −7.472 12.456 1.00 24.93 B C ATOM 1526 CG ASN B 106 60.034 −6.265 13.110 1.00 25.53 B C ATOM 1527 OD1 ASN B 106 58.856 −6.264 13.458 1.00 26.27 B O ATOM 1528 ND2 ASN B 106 60.834 −5.217 13.277 1.00 25.70 B N ATOM 1529 C ASN B 106 61.233 −8.611 10.358 1.00 23.49 B C ATOM 1530 O ASN B 106 62.338 −8.827 10.852 1.00 22.73 B O ATOM 1531 N LEU B 107 60.789 −9.282 9.304 1.00 22.79 B N ATOM 1532 CA LEU B 107 61.654 −10.284 8.708 1.00 24.03 B C ATOM 1533 CB LEU B 107 61.743 −11.516 9.618 1.00 22.22 B C ATOM 1534 CG LEU B 107 60.453 −12.292 9.894 1.00 21.52 B C ATOM 1535 CD1 LEU B 107 59.996 −13.035 8.634 1.00 16.87 B C ATOM 1536 CD2 LEU B 107 60.700 −13.257 11.052 1.00 17.96 B C ATOM 1537 C LEU B 107 61.273 −10.717 7.313 1.00 24.68 B C ATOM 1538 O LEU B 107 60.229 −10.348 6.784 1.00 25.72 B O ATOM 1539 N VAL B 108 62.150 −11.511 6.724 1.00 25.61 B N ATOM 1540 CA VAL B 108 61.936 −12.031 5.390 1.00 27.06 B C ATOM 1541 CB VAL B 108 63.058 −11.586 4.444 1.00 25.47 B C ATOM 1542 CG1 VAL B 108 62.957 −12.341 3.135 1.00 24.63 B C ATOM 1543 CG2 VAL B 108 62.969 −10.086 4.222 1.00 22.69 B C ATOM 1544 C VAL B 108 61.933 −13.545 5.497 1.00 28.76 B C ATOM 1545 O VAL B 108 62.874 −14.138 6.029 1.00 28.49 B O ATOM 1546 N VAL B 109 60.864 −14.167 5.014 1.00 30.58 B N ATOM 1547 CA VAL B 109 60.759 −15.614 5.072 1.00 32.56 B C ATOM 1548 CB VAL B 109 59.313 −16.078 4.832 1.00 31.31 B C ATOM 1549 CG1 VAL B 109 59.278 −17.576 4.574 1.00 31.62 B C ATOM 1550 CG2 VAL B 109 58.464 −15.748 6.052 1.00 30.66 B C ATOM 1551 C VAL B 109 61.677 −16.244 4.044 1.00 35.10 B C ATOM 1552 O VAL B 109 61.527 −16.022 2.849 1.00 35.31 B O ATOM 1553 N VAL B 110 62.644 −17.016 4.526 1.00 39.13 B N ATOM 1554 CA VAL B 110 63.585 −17.692 3.650 1.00 42.88 B C ATOM 1555 CB VAL B 110 64.704 −18.382 4.456 1.00 41.38 B C ATOM 1556 CG1 VAL B 110 65.680 −19.047 3.511 1.00 40.84 B C ATOM 1557 CG2 VAL B 110 65.423 −17.365 5.326 1.00 40.23 B C ATOM 1558 C VAL B 110 62.807 −18.743 2.871 1.00 47.10 B C ATOM 1559 O VAL B 110 62.454 −19.793 3.411 1.00 47.39 B O ATOM 1560 N ASN B 111 62.520 −18.443 1.608 1.00 51.94 B N ATOM 1561 CA ASN B 111 61.778 −19.364 0.753 1.00 56.97 B C ATOM 1562 CB ASN B 111 61.176 −18.631 −0.459 1.00 60.23 B C ATOM 1563 CG ASN B 111 59.906 −17.853 −0.112 1.00 63.33 B C ATOM 1564 OD1 ASN B 111 58.976 −18.393 0.498 1.00 64.57 B O ATOM 1565 ND2 ASN B 111 59.860 −16.584 −0.513 1.00 63.31 B N ATOM 1566 C ASN B 111 62.689 −20.483 0.271 1.00 58.44 B C ATOM 1567 O ASN B 111 63.054 −20.463 −0.929 1.00 58.94 B O ATOM 1568 OXT ASN B 111 63.031 −21.352 1.109 1.00 59.32 B O ATOM 1569 C01 DCB A 1 44.995 14.553 26.771 1.00 19.45 INH1 C ATOM 1570 C02 DCB A 1 45.473 14.089 25.525 1.00 19.40 INH1 C ATOM 1571 C03 DCB A 1 46.459 13.078 25.479 1.00 18.81 INH1 C ATOM 1572 C04 DCB A 1 46.993 12.532 26.669 1.00 18.15 INH1 C ATOM 1573 C05 DCB A 1 46.522 12.992 27.934 1.00 18.26 INH1 C ATOM 1574 C06 DCB A 1 45.507 14.004 28.010 1.00 19.06 INH1 C ATOM 1575 C07 DCB A 1 44.960 14.431 29.387 1.00 18.98 INH1 C ATOM 1576 C08 DCB A 1 44.482 15.900 29.479 1.00 18.21 INH1 C ATOM 1577 O09 DCB A 1 45.128 16.883 29.170 1.00 18.92 INH1 O ATOM 1578 O10 DCB A 1 43.224 16.042 29.950 1.00 18.35 INH1 O ATOM 1579 N11 DCB A 1 43.871 13.399 29.794 1.00 19.31 INH1 N ATOM 1580 C12 DCB A 1 42.739 13.151 28.806 1.00 20.29 INH1 C ATOM 1581 C13 DCB A 1 42.714 11.792 28.013 1.00 21.02 INH1 C ATOM 1582 C14 DCB A 1 41.502 11.204 27.521 1.00 22.07 INH1 C ATOM 1583 C15 DCB A 1 41.529 9.989 26.772 1.00 21.64 INH1 C ATOM 1584 C16 DCB A 1 42.766 9.364 26.518 1.00 19.81 INH1 C ATOM 1585 CL7 DCB A 1 42.851 7.955 25.617 1.00 21.03 INH1 CL ATOM 1586 C18 DCB A 1 43.944 9.900 26.994 1.00 21.69 INH1 C ATOM 1587 C19 DCB A 1 43.911 11.091 27.724 1.00 21.17 INH1 C ATOM 1588 C20 DCB A 1 41.375 13.473 29.512 1.00 20.86 INH1 C ATOM 1589 O21 DCB A 1 40.624 14.335 29.051 1.00 23.97 INH1 O ATOM 1590 N22 DCB A 1 40.986 12.802 30.650 1.00 19.65 INH1 N ATOM 1591 C23 DCB A 1 41.675 11.792 31.325 1.00 20.23 INH1 C ATOM 1592 C24 DCB A 1 43.086 11.753 31.524 1.00 19.69 INH1 C ATOM 1593 C25 DCB A 1 44.037 12.771 31.037 1.00 19.00 INH1 C ATOM 1594 O26 DCB A 1 44.998 13.033 31.782 1.00 17.63 INH1 O ATOM 1595 C27 DCB A 1 43.671 10.672 32.209 1.00 20.56 INH1 C ATOM 1596 C28 DCB A 1 42.884 9.636 32.703 1.00 21.72 INH1 C ATOM 1597 I29 DCB A 1 43.831 8.120 33.679 1.00 27.66 INH1 I ATOM 1598 C30 DCB A 1 41.486 9.633 32.527 1.00 20.49 INH1 C ATOM 1599 C31 DCB A 1 40.878 10.720 31.834 1.00 20.28 INH1 C ATOM 1600 CL4 DCB A 1 46.990 12.507 23.963 1.00 22.77 INH1 CL ATOM 1601 C01 DCB B 1 55.033 −18.308 22.747 1.00 19.12 INH2 C ATOM 1602 C02 DCB B 1 54.627 −17.796 21.500 1.00 20.84 INH2 C ATOM 1603 C03 DCB B 1 53.586 −16.858 21.435 1.00 19.81 INH2 C ATOM 1604 C04 DCB B 1 52.928 −16.427 22.609 1.00 19.80 INH2 C ATOM 1605 C05 DCB B 1 53.324 −16.933 23.869 1.00 17.07 INH2 C ATOM 1606 C06 DCB B 1 54.391 −17.878 23.966 1.00 19.91 INH2 C ATOM 1607 C07 DCB B 1 54.852 −18.369 25.359 1.00 20.82 INH2 C ATOM 1608 C08 DCB B 1 55.351 −19.841 25.402 1.00 22.94 INH2 C ATOM 1609 O09 DCB B 1 54.794 −20.807 24.886 1.00 25.59 INH2 O ATOM 1610 O10 DCB B 1 56.509 −20.014 26.080 1.00 23.06 INH2 O ATOM 1611 N11 DCB B 1 55.878 −17.334 25.899 1.00 19.57 INH2 N ATOM 1612 C12 DCB B 1 57.080 −17.004 25.022 1.00 20.13 INH2 C ATOM 1613 C13 DCB B 1 57.132 −15.603 24.277 1.00 18.49 INH2 C ATOM 1614 C14 DCB B 1 58.375 −14.960 23.931 1.00 18.55 INH2 C ATOM 1615 C15 DCB B 1 58.397 −13.717 23.229 1.00 17.27 INH2 C ATOM 1616 C16 DCB B 1 57.174 −13.094 22.866 1.00 17.55 INH2 C ATOM 1617 CL7 DCB B 1 57.162 −11.622 22.002 1.00 15.37 INH2 CL ATOM 1618 C18 DCB B 1 55.956 −13.690 23.201 1.00 18.48 INH2 C ATOM 1619 C19 DCB B 1 55.943 −14.920 23.892 1.00 16.55 INH2 C ATOM 1620 C20 DCB B 1 58.392 −17.329 25.826 1.00 20.23 INH2 C ATOM 1621 O21 DCB B 1 59.185 −18.162 25.394 1.00 25.59 INH2 O ATOM 1622 N22 DCB B 1 58.683 −16.699 27.020 1.00 19.93 INH2 N ATOM 1623 C23 DCB B 1 57.918 −15.728 27.690 1.00 20.26 INH2 C ATOM 1624 C24 DCB B 1 56.490 −15.740 27.776 1.00 20.17 INH2 C ATOM 1625 C25 DCB B 1 55.600 −16.767 27.159 1.00 20.53 INH2 C ATOM 1626 O26 DCB B 1 54.590 −17.088 27.811 1.00 21.53 INH2 O ATOM 1627 C27 DCB B 1 55.819 −14.708 28.470 1.00 21.53 INH2 C ATOM 1628 C28 DCB B 1 56.530 −13.674 29.077 1.00 21.73 INH2 C ATOM 1629 I29 DCB B 1 55.453 −12.232 30.059 1.00 25.57 INH2 I ATOM 1630 C30 DCB B 1 57.947 −13.629 29.011 1.00 19.97 INH2 C ATOM 1631 C31 DCB B 1 58.640 −14.661 28.313 1.00 19.37 INH2 C ATOM 1632 CL4 DCB B 1 53.130 −16.225 19.915 1.00 26.49 INH2 CL ATOM 1633 O HOH W 1 50.080 10.720 15.348 1.00 7.59 W O ATOM 1634 O HOH W 2 38.444 13.118 31.386 1.00 5.35 W O ATOM 1635 O HOH W 3 47.443 −10.725 13.437 1.00 14.91 W O ATOM 1636 O HOH W 4 29.146 13.552 26.964 1.00 15.71 W O ATOM 1637 O HOH W 5 70.995 −16.794 24.450 1.00 16.59 W O ATOM 1638 O HOH W 6 50.735 13.798 13.410 1.00 13.16 W O ATOM 1639 O HOH W 7 49.418 −5.142 21.249 1.00 15.76 W O ATOM 1640 O HOH W 8 46.736 −6.924 18.802 1.00 29.90 W O ATOM 1641 O HOH W 9 46.333 18.271 10.887 1.00 21.24 W O ATOM 1642 O HOH W 10 44.953 1.508 16.559 1.00 16.86 W O ATOM 1643 O HOH W 11 50.119 1.302 17.902 1.00 10.56 W O ATOM 1644 O HOH W 12 51.688 −2.161 31.579 1.00 16.65 W O ATOM 1645 O HOH W 13 42.377 −8.932 17.709 1.00 34.03 W O ATOM 1646 O HOH W 14 37.372 14.678 29.417 1.00 16.58 W O ATOM 1647 O HOH W 15 36.788 2.596 14.963 1.00 19.58 W O ATOM 1648 O HOH W 16 55.277 13.766 18.294 1.00 13.87 W O ATOM 1649 O HOH W 17 54.375 11.978 22.811 1.00 27.18 W O ATOM 1650 O HOH W 18 31.627 5.760 10.477 1.00 26.87 W O ATOM 1651 O HOH W 19 73.374 −18.273 9.466 1.00 13.88 W O ATOM 1652 O HOH W 20 69.316 −11.815 9.399 1.00 15.93 W O ATOM 1653 O HOH W 21 39.407 16.870 29.919 1.00 27.45 W O ATOM 1654 O HOH W 22 26.437 13.074 9.218 1.00 27.45 W O ATOM 1655 O HOH W 23 48.241 −7.611 22.677 1.00 27.74 W O ATOM 1656 O HOH W 24 62.618 −18.064 25.960 1.00 14.87 W O ATOM 1657 O HOH W 25 41.190 −7.082 20.138 1.00 33.52 W O ATOM 1658 O HOH W 26 68.699 −15.754 29.529 1.00 30.32 W O ATOM 1659 O HOH W 27 31.174 12.013 32.184 1.00 23.09 W O ATOM 1660 O HOH W 28 59.516 −20.585 21.234 1.00 23.18 W O ATOM 1661 O HOH W 29 63.647 −5.623 12.316 1.00 24.20 W O ATOM 1662 O HOH W 30 46.038 −15.942 18.815 1.00 20.52 W O ATOM 1663 O HOH W 31 29.060 3.628 15.693 1.00 24.99 W O ATOM 1664 O HOH W 32 64.750 −2.147 9.054 1.00 18.00 W O ATOM 1665 O HOH W 33 60.948 −20.101 26.368 1.00 21.11 W O ATOM 1666 O HOH W 34 33.523 −2.988 26.616 1.00 26.29 W O ATOM 1667 O HOH W 35 52.195 4.178 26.652 1.00 19.95 W O ATOM 1668 O HOH W 36 58.440 −12.039 3.658 1.00 18.21 W O ATOM 1669 O HOH W 37 55.725 −4.051 36.348 1.00 24.18 W O ATOM 1670 O HOH W 38 50.596 −17.942 26.802 1.00 25.64 W O ATOM 1671 O HOH W 39 71.444 −18.646 17.806 1.00 21.69 W O ATOM 1672 O HOH W 40 27.895 16.214 12.305 1.00 17.52 W O ATOM 1673 O HOH W 41 63.206 −0.871 28.592 1.00 33.36 W O ATOM 1674 O HOH W 42 44.097 −6.181 23.040 1.00 26.08 W O ATOM 1675 O HOH W 43 60.959 −16.823 28.199 1.00 22.71 W O ATOM 1676 O HOH W 44 41.993 0.362 10.843 1.00 25.21 W O ATOM 1677 O HOH W 45 53.471 14.144 25.683 1.00 15.46 W O ATOM 1678 O HOH W 46 77.169 −14.015 22.972 1.00 30.41 W O ATOM 1679 O HOH W 47 51.042 0.090 12.306 1.00 25.87 W O ATOM 1680 O HOH W 48 53.856 2.794 19.440 1.00 15.61 W O ATOM 1681 O HOH W 49 51.232 3.940 19.368 1.00 15.09 W O ATOM 1682 O HOH W 50 54.070 9.295 22.941 1.00 24.70 W O END

TABLE 2 compound 876273 ([8-Chloro-3-(4-chloro-phenyl)-7-iodo-2,5- dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro- phenyl)-acetic acid) REMARK coordinates from restrained individual B-factor refinement REMARK refinement resolution: 25-2.6 A REMARK starting r = 0.2563 free_r = 0.2787 REMARK final r = 0.2553 free_r = 0.2761 REMARK B rmsd for bonded mainchain atoms = 1.483 target = 1.5 REMARK B rmsd for bonded sidechain atoms = 1.740 target = 2.0 REMARK B rmsd for angle mainchain atoms = 2.593 target = 2.0 REMARK B rmsd for angle sidechain atoms = 2.780 target = 2.5 REMARK rweight = 0.1000 (with wa = 3.71696) REMARK target = mlf steps = 30 REMARK sg = P4(3)2(1)2 a = 54.3 b = 54.3 c = 83.3 alpha = 90 beta = 90 gamma = 90 REMARK parameter file 1 : MSI_CNX_TOPPAR: protein_rep.param REMARK parameter file 2 : ../cid.par REMARK molecular structure file: recycle.psf REMARK input coordinates: anneal_9.pdb REMARK reflection file = ../M876273_2_P43212.cv REMARK ncs = none REMARK B-correction resolution: 6.0-2.6 REMARK initial B-factor correction applied to fobs: REMARK B11 = −1.189 B22 = −1.189 B33 = 2.379 REMARK B12 = 0.000 B13 = 0.000 B23 = 0.000 REMARK B-factor correction applied to coordinate array B:  −0.119 REMARK bulk solvent: (Mask) density level = 0.341945 e/A{circumflex over ( )}3, B-factor = 22.3925 A{circumflex over ( )}2 REMARK reflections with |Fobs|/sigma_F <0.0 rejected REMARK reflections with |Fobs| >10000 * rms(Fobs) rejected REMARK theoretical total number of ref1. in resol. range: 4173 (100.0%) REMARK number of unobserved reflections (no entry or |F| = 0): 9 (0.2%) REMARK number of reflections rejected: 0 (  0.0% ) REMARK total number of reflections used: 4164 (  99.8% ) REMARK number of reflections in working set: 3737 ( 89.6% ) REMARK number of reflections in test set: 427 ( 10.2% ) CRYST1  54.300  54.300  83.300  90.00  90.00  90.00 P 43 21 2 REMARK FILENAME = “bindividual.pdb” REMARK Written by CNX VERSION: 2000.12 ATOM 1 C GLY A 16 50.842 45.566 39.472 1.00 68.15 A C ATOM 2 O GLY A 16 49.884 45.429 40.244 1.00 68.22 A O ATOM 3 N GLY A 16 51.272 44.956 37.085 1.00 67.11 A N ATOM 4 CA GLY A 16 51.225 44.463 38.498 1.00 67.90 A C ATOM 5 N SER A 17 51.601 46.662 39.435 1.00 67.05 A N ATOM 6 CA SER A 17 51.358 47.819 40.296 1.00 64.73 A C ATOM 7 CB SER A 17 52.359 47.851 41.458 1.00 65.01 A C ATOM 8 OG SER A 17 52.175 46.743 42.330 1.00 63.84 A O ATOM 9 C SER A 17 51.495 49.080 39.449 1.00 62.82 A C ATOM 10 O SER A 17 51.039 50.157 39.837 1.00 62.75 A O ATOM 11 N GLN A 18 52.130 48.925 38.289 1.00 60.52 A N ATOM 12 CA GLN A 18 52.323 50.023 37.346 1.00 57.89 A C ATOM 13 CB GLN A 18 53.377 49.652 36.306 1.00 57.50 A C ATOM 14 CG GLN A 18 54.800 49.725 36.791 1.00 57.38 A C ATOM 15 CD GLN A 18 55.786 49.390 35.687 1.00 58.16 A C ATOM 16 OE1 GLN A 18 55.675 49.892 34.565 1.00 56.84 A O ATOM 17 NE2 GLN A 18 56.761 48.543 36.002 1.00 58.44 A N ATOM 18 C GLN A 18 51.013 50.299 36.620 1.00 55.87 A C ATOM 19 O GLN A 18 50.763 51.414 36.157 1.00 55.83 A O ATOM 20 N ILE A 19 50.187 49.261 36.524 1.00 52.87 A N ATOM 21 CA ILE A 19 48.898 49.337 35.850 1.00 50.05 A C ATOM 22 CB ILE A 19 48.721 48.131 34.883 1.00 48.06 A C ATOM 23 CG2 ILE A 19 47.404 48.239 34.138 1.00 48.17 A C ATOM 24 CG1 ILE A 19 49.885 48.069 33.889 1.00 45.44 A C ATOM 25 CD1 ILE A 19 49.939 49.218 32.921 1.00 43.26 A C ATOM 26 C ILE A 19 47.769 49.319 36.884 1.00 49.72 A C ATOM 27 O ILE A 19 47.863 48.631 37.902 1.00 49.03 A O ATOM 28 N PRO A 20 46.694 50.095 36.643 1.00 49.57 A N ATOM 29 CD PRO A 20 46.609 51.167 35.636 1.00 49.58 A C ATOM 30 CA PRO A 20 45.546 50.162 37.553 1.00 49.39 A C ATOM 31 CB PRO A 20 44.693 51.271 36.949 1.00 48.67 A C ATOM 32 CG PRO A 20 45.704 52.159 36.318 1.00 48.94 A C ATOM 33 C PRO A 20 44.784 48.836 37.628 1.00 49.97 A C ATOM 34 O PRO A 20 44.551 48.184 36.606 1.00 50.18 A O ATOM 35 N ALA A 21 44.399 48.446 38.840 1.00 49.45 A N ATOM 36 CA ALA A 21 43.660 47.207 39.057 1.00 49.81 A C ATOM 37 CB ALA A 21 43.252 47.094 40.528 1.00 49.85 A C ATOM 38 C ALA A 21 42.419 47.133 38.160 1.00 49.65 A C ATOM 39 O ALA A 21 42.160 46.112 37.517 1.00 49.33 A O ATOM 40 N SER A 22 41.650 48.217 38.125 1.00 48.76 A N ATOM 41 CA SER A 22 40.451 48.260 37.302 1.00 47.75 A C ATOM 42 CB SER A 22 39.873 49.678 37.296 1.00 47.15 A C ATOM 43 OG SER A 22 40.857 50.625 36.915 1.00 48.43 A O ATOM 44 C SER A 22 40.792 47.816 35.877 1.00 46.34 A C ATOM 45 O SER A 22 40.029 47.083 35.242 1.00 45.89 A O ATOM 46 N GLU A 23 41.947 48.251 35.384 1.00 44.68 A N ATOM 47 CA GLU A 23 42.375 47.887 34.040 1.00 43.25 A C ATOM 48 CB GLU A 23 43.526 48.771 33.588 1.00 42.16 A C ATOM 49 CG GLU A 23 43.939 48.525 32.164 1.00 40.86 A C ATOM 50 CD GLU A 23 44.747 49.671 31.612 1.00 40.82 A C ATOM 51 OE1 GLU A 23 45.613 50.189 32.344 1.00 41.52 A O ATOM 52 OE2 GLU A 23 44.523 50.054 30.448 1.00 41.56 A O ATOM 53 C GLU A 23 42.790 46.428 33.991 1.00 42.01 A C ATOM 54 O GLU A 23 42.419 45.701 33.076 1.00 42.32 A O ATOM 55 N GLN A 24 43.561 45.998 34.977 1.00 41.29 A N ATOM 56 CA GLN A 24 43.973 44.610 35.027 1.00 42.07 A C ATOM 57 CB GLN A 24 44.762 44.334 36.314 1.00 41.13 A C ATOM 58 CG GLN A 24 46.206 44.813 36.250 1.00 42.57 A C ATOM 59 CD GLN A 24 46.978 44.602 37.546 1.00 43.91 A C ATOM 60 OE1 GLN A 24 46.823 43.580 38.225 1.00 44.84 A O ATOM 61 NE2 GLN A 24 47.831 45.564 37.884 1.00 43.17 A N ATOM 62 C GLN A 24 42.714 43.747 34.984 1.00 43.32 A C ATOM 63 O GLN A 24 42.750 42.596 34.541 1.00 43.40 A O ATOM 64 N GLU A 25 41.596 44.326 35.423 1.00 44.62 A N ATOM 65 CA GLU A 25 40.314 43.618 35.464 1.00 44.92 A C ATOM 66 CB GLU A 25 39.471 44.123 36.642 1.00 48.33 A C ATOM 67 CG GLU A 25 40.216 44.254 37.972 1.00 53.04 A C ATOM 68 CD GLU A 25 40.899 42.969 38.423 1.00 55.79 A C ATOM 69 OE1 GLU A 25 41.474 42.972 39.533 1.00 57.11 A O ATOM 70 OE2 GLU A 25 40.869 41.961 37.681 1.00 57.84 A O ATOM 71 C GLU A 25 39.472 43.697 34.184 1.00 42.75 A C ATOM 72 O GLU A 25 38.563 42.887 33.992 1.00 42.62 A O ATOM 73 N THR A 26 39.760 44.666 33.319 1.00 40.18 A N ATOM 74 CA THR A 26 39.013 44.813 32.067 1.00 38.13 A C ATOM 75 CB THR A 26 39.714 45.803 31.100 1.00 37.92 A C ATOM 76 OG1 THR A 26 40.061 47.002 31.803 1.00 37.02 A O ATOM 77 CG2 THR A 26 38.798 46.161 29.945 1.00 36.76 A C ATOM 78 C THR A 26 38.897 43.456 31.367 1.00 36.79 A C ATOM 79 O THR A 26 39.859 42.693 31.321 1.00 36.47 A O ATOM 80 N LEU A 27 37.715 43.152 30.841 1.00 36.63 A N ATOM 81 CA LEU A 27 37.490 41.887 30.138 1.00 35.77 A C ATOM 82 CB LEU A 27 36.035 41.429 30.291 1.00 36.16 A C ATOM 83 CG LEU A 27 35.799 39.909 30.293 1.00 38.05 A C ATOM 84 CD1 LEU A 27 36.293 39.313 31.617 1.00 36.12 A C ATOM 85 CD2 LEU A 27 34.305 39.610 30.112 1.00 38.41 A C ATOM 86 C LEU A 27 37.808 42.130 28.665 1.00 34.52 A C ATOM 87 O LEU A 27 37.395 43.139 28.090 1.00 33.72 A O ATOM 88 N VAL A 28 38.540 41.204 28.054 1.00 33.53 A N ATOM 89 CA VAL A 28 38.941 41.364 26.662 1.00 32.88 A C ATOM 90 CB VAL A 28 40.420 41.848 26.589 1.00 32.86 A C ATOM 91 CG1 VAL A 28 40.570 43.182 27.302 1.00 31.21 A C ATOM 92 CG2 VAL A 28 41.340 40.821 27.242 1.00 33.40 A C ATOM 93 C VAL A 28 38.792 40.107 25.802 1.00 31.29 A C ATOM 94 O VAL A 28 38.708 38.992 26.314 1.00 30.99 A O ATOM 95 N ARG A 29 38.754 40.312 24.489 1.00 29.80 A N ATOM 96 CA ARG A 29 38.641 39.224 23.528 1.00 28.94 A C ATOM 97 CB ARG A 29 37.379 39.371 22.685 1.00 33.14 A C ATOM 98 CG ARG A 29 36.132 38.818 23.326 1.00 38.54 A C ATOM 99 CD ARG A 29 34.905 39.188 22.511 1.00 43.39 A C ATOM 100 NE ARG A 29 33.712 38.549 23.051 1.00 47.28 A N ATOM 101 CZ ARG A 29 33.397 37.276 22.843 1.00 49.30 A C ATOM 102 NH1 ARG A 29 34.185 36.511 22.093 1.00 49.75 A N ATOM 103 NH2 ARG A 29 32.309 36.763 23.405 1.00 50.29 A N ATOM 104 C ARG A 29 39.842 39.254 22.602 1.00 26.43 A C ATOM 105 O ARG A 29 39.935 40.121 21.727 1.00 25.41 A O ATOM 106 N PRO A 30 40.785 38.315 22.789 1.00 24.69 A N ATOM 107 CD PRO A 30 40.798 37.274 23.830 1.00 23.43 A C ATOM 108 CA PRO A 30 41.995 38.234 21.958 1.00 23.00 A C ATOM 109 CB PRO A 30 42.826 37.151 22.643 1.00 21.72 A C ATOM 110 CG PRO A 30 42.261 37.064 24.025 1.00 22.48 A C ATOM 111 C PRO A 30 41.620 37.801 20.544 1.00 22.20 A C ATOM 112 O PRO A 30 40.663 37.050 20.360 1.00 22.27 A O ATOM 113 N LYS A 31 42.365 38.273 19.551 1.00 21.65 A N ATOM 114 CA LYS A 31 42.118 37.880 18.166 1.00 19.51 A C ATOM 115 CB LYS A 31 42.825 38.839 17.210 1.00 19.68 A C ATOM 116 CG LYS A 31 42.364 40.279 17.348 1.00 20.82 A C ATOM 117 CD LYS A 31 43.115 41.174 16.376 1.00 22.74 A C ATOM 118 CE LYS A 31 42.641 42.630 16.435 1.00 20.68 A C ATOM 119 NZ LYS A 31 43.356 43.433 15.396 1.00 21.75 A N ATOM 120 C LYS A 31 42.666 36.454 18.011 1.00 18.36 A C ATOM 121 O LYS A 31 43.441 35.983 18.847 1.00 17.38 A O ATOM 122 N PRO A 32 42.291 35.760 16.930 1.00 17.15 A N ATOM 123 CD PRO A 32 41.612 36.293 15.736 1.00 16.30 A C ATOM 124 CA PRO A 32 42.737 34.387 16.684 1.00 16.70 A C ATOM 125 CB PRO A 32 42.392 34.182 15.213 1.00 16.53 A C ATOM 126 CG PRO A 32 41.180 35.032 15.044 1.00 16.35 A C ATOM 127 C PRO A 32 44.198 34.043 16.997 1.00 16.73 A C ATOM 128 O PRO A 32 44.470 33.062 17.695 1.00 17.12 A O ATOM 129 N LEU A 33 45.137 34.830 16.483 1.00 14.62 A N ATOM 130 CA LEU A 33 46.540 34.538 16.724 1.00 13.59 A C ATOM 131 CB LEU A 33 47.425 35.427 15.843 1.00 15.36 A C ATOM 132 CG LEU A 33 48.097 34.759 14.626 1.00 13.91 A C ATOM 133 CD1 LEU A 33 47.597 33.319 14.406 1.00 13.51 A C ATOM 134 CD2 LEU A 33 47.838 35.609 13.411 1.00 8.87 A C ATOM 135 C LEU A 33 46.936 34.641 18.189 1.00 13.14 A C ATOM 136 O LEU A 33 47.545 33.724 18.715 1.00 12.37 A O ATOM 137 N LEU A 34 46.610 35.744 18.856 1.00 14.58 A N ATOM 138 CA LEU A 34 46.930 35.859 20.279 1.00 13.84 A C ATOM 139 CB LEU A 34 46.540 37.236 20.826 1.00 13.73 A C ATOM 140 CG LEU A 34 46.613 37.449 22.347 1.00 10.65 A C ATOM 141 CD1 LEU A 34 48.041 37.367 22.818 1.00 9.38 A C ATOM 142 CD2 LEU A 34 46.029 38.795 22.701 1.00 11.47 A C ATOM 143 C LEU A 34 46.158 34.771 21.039 1.00 15.75 A C ATOM 144 O LEU A 34 46.678 34.176 21.975 1.00 16.50 A O ATOM 145 N LEU A 35 44.917 34.506 20.635 1.00 17.07 A N ATOM 146 CA LEU A 35 44.125 33.469 21.295 1.00 18.94 A C ATOM 147 CB LEU A 35 42.720 33.381 20.686 1.00 16.70 A C ATOM 148 CG LEU A 35 41.753 32.424 21.391 1.00 14.51 A C ATOM 149 CD1 LEU A 35 41.542 32.888 22.825 1.00 13.73 A C ATOM 150 CD2 LEU A 35 40.425 32.379 20.653 1.00 13.01 A C ATOM 151 C LEU A 35 44.815 32.094 21.218 1.00 20.66 A C ATOM 152 O LEU A 35 44.668 31.276 22.133 1.00 21.36 A O ATOM 153 N LYS A 36 45.563 31.845 20.140 1.00 20.77 A N ATOM 154 CA LYS A 36 46.279 30.581 19.979 1.00 22.28 A C ATOM 155 CB LYS A 36 46.792 30.398 18.547 1.00 23.62 A C ATOM 156 CG LYS A 36 45.782 29.781 17.586 1.00 28.23 A C ATOM 157 CD LYS A 36 46.444 28.754 16.647 1.00 30.56 A C ATOM 158 CE LYS A 36 47.556 29.366 15.789 1.00 32.43 A C ATOM 159 NZ LYS A 36 48.108 28.414 14.778 1.00 31.16 A N ATOM 160 C LYS A 36 47.461 30.504 20.937 1.00 23.86 A C ATOM 161 O LYS A 36 47.716 29.451 21.537 1.00 26.24 A O ATOM 162 N LEU A 37 48.196 31.603 21.076 1.00 23.16 A N ATOM 163 CA LEU A 37 49.332 31.612 21.994 1.00 24.32 A C ATOM 164 CB LEU A 37 49.920 33.019 22.134 1.00 25.18 A C ATOM 165 CG LEU A 37 50.647 33.606 20.934 1.00 27.89 A C ATOM 166 CD1 LEU A 37 51.343 34.901 21.343 1.00 28.24 A C ATOM 167 CD2 LEU A 37 51.659 32.597 20.431 1.00 28.07 A C ATOM 168 C LEU A 37 48.884 31.144 23.377 1.00 23.05 A C ATOM 169 O LEU A 37 49.526 30.304 24.003 1.00 20.34 A O ATOM 170 N LEU A 38 47.770 31.706 23.834 1.00 23.36 A N ATOM 171 CA LEU A 38 47.218 31.399 25.139 1.00 24.58 A C ATOM 172 CB LEU A 38 46.036 32.322 25.447 1.00 21.20 A C ATOM 173 CG LEU A 38 46.216 33.821 25.189 1.00 19.16 A C ATOM 174 CD1 LEU A 38 44.954 34.538 25.619 1.00 16.77 A C ATOM 175 CD2 LEU A 38 47.420 34.370 25.950 1.00 18.04 A C ATOM 176 C LEU A 38 46.772 29.950 25.241 1.00 27.20 A C ATOM 177 O LEU A 38 46.970 29.309 26.273 1.00 29.33 A O ATOM 178 N LYS A 39 46.175 29.419 24.182 1.00 28.13 A N ATOM 179 CA LYS A 39 45.720 28.041 24.241 1.00 29.30 A C ATOM 180 CB LYS A 39 44.782 27.741 23.071 1.00 28.63 A C ATOM 181 CG LYS A 39 43.532 28.596 23.123 1.00 28.78 A C ATOM 182 CD LYS A 39 42.451 28.113 22.184 1.00 27.98 A C ATOM 183 CE LYS A 39 41.239 29.021 22.270 1.00 26.89 A C ATOM 184 NZ LYS A 39 40.089 28.444 21.537 1.00 27.11 A N ATOM 185 C LYS A 39 46.884 27.062 24.270 1.00 30.33 A C ATOM 186 O LYS A 39 46.787 25.998 24.883 1.00 31.74 A O ATOM 187 N SER A 40 47.993 27.428 23.633 1.00 30.27 A N ATOM 188 CA SER A 40 49.169 26.559 23.607 1.00 29.62 A C ATOM 189 CB SER A 40 50.280 27.175 22.735 1.00 28.81 A C ATOM 190 OG SER A 40 50.904 28.292 23.357 1.00 26.68 A O ATOM 191 C SER A 40 49.701 26.301 25.020 1.00 29.48 A C ATOM 192 O SER A 40 50.396 25.316 25.254 1.00 29.59 A O ATOM 193 N VAL A 41 49.374 27.186 25.958 1.00 30.35 A N ATOM 194 CA VAL A 41 49.827 27.044 27.345 1.00 30.76 A C ATOM 195 CB VAL A 41 50.717 28.252 27.799 1.00 30.64 A C ATOM 196 CG1 VAL A 41 52.087 28.184 27.125 1.00 29.00 A C ATOM 197 CG2 VAL A 41 50.030 29.574 27.470 1.00 28.32 A C ATOM 198 C VAL A 41 48.678 26.891 28.345 1.00 32.02 A C ATOM 199 O VAL A 41 48.691 27.500 29.419 1.00 31.05 A O ATOM 200 N GLY A 42 47.675 26.092 27.983 1.00 33.77 A N ATOM 201 CA GLY A 42 46.563 25.862 28.889 1.00 36.14 A C ATOM 202 C GLY A 42 45.260 26.597 28.641 1.00 38.10 A C ATOM 203 O GLY A 42 44.201 25.971 28.653 1.00 40.02 A O ATOM 204 N ALA A 43 45.317 27.912 28.432 1.00 38.97 A N ATOM 205 CA ALA A 43 44.107 28.703 28.203 1.00 39.16 A C ATOM 206 CB ALA A 43 44.459 30.022 27.518 1.00 38.86 A C ATOM 207 C ALA A 43 43.080 27.938 27.375 1.00 39.94 A C ATOM 208 O ALA A 43 43.437 27.164 26.485 1.00 40.04 A O ATOM 209 N GLN A 44 41.802 28.155 27.675 1.00 41.54 A N ATOM 210 CA GLN A 44 40.733 27.475 26.955 1.00 42.78 A C ATOM 211 CB GLN A 44 40.609 26.037 27.466 1.00 45.11 A C ATOM 212 CG GLN A 44 40.573 25.913 28.984 1.00 47.61 A C ATOM 213 CD GLN A 44 40.868 24.493 29.456 1.00 49.56 A C ATOM 214 OE1 GLN A 44 40.913 24.221 30.662 1.00 49.35 A O ATOM 215 NE2 GLN A 44 41.075 23.581 28.506 1.00 49.08 A N ATOM 216 C GLN A 44 39.379 28.183 27.030 1.00 42.23 A C ATOM 217 O GLN A 44 38.355 27.557 27.322 1.00 42.70 A O ATOM 218 N LYS A 45 39.391 29.488 26.763 1.00 40.15 A N ATOM 219 CA LYS A 45 38.184 30.307 26.765 1.00 37.90 A C ATOM 220 CB LYS A 45 38.085 31.150 28.034 1.00 39.62 A C ATOM 221 CG LYS A 45 38.193 30.392 29.341 1.00 41.18 A C ATOM 222 CD LYS A 45 37.768 31.288 30.502 1.00 42.96 A C ATOM 223 CE LYS A 45 38.491 32.629 30.473 1.00 45.64 A C ATOM 224 NZ LYS A 45 38.045 33.556 31.559 1.00 48.08 A N ATOM 225 C LYS A 45 38.296 31.254 25.585 1.00 36.61 A C ATOM 226 O LYS A 45 39.258 31.183 24.822 1.00 36.82 A O ATOM 227 N ASP A 46 37.323 32.149 25.448 1.00 34.69 A N ATOM 228 CA ASP A 46 37.332 33.128 24.368 1.00 33.64 A C ATOM 229 CB ASP A 46 36.015 33.106 23.577 1.00 35.21 A C ATOM 230 CG ASP A 46 35.826 31.828 22.778 1.00 36.60 A C ATOM 231 OD1 ASP A 46 36.819 31.326 22.204 1.00 35.63 A O ATOM 232 OD2 ASP A 46 34.677 31.337 22.712 1.00 36.79 A O ATOM 233 C ASP A 46 37.529 34.526 24.935 1.00 32.32 A C ATOM 234 O ASP A 46 38.032 35.419 24.249 1.00 33.06 A O ATOM 235 N THR A 47 37.118 34.715 26.186 1.00 30.30 A N ATOM 236 CA THR A 47 37.233 36.012 26.850 1.00 27.52 A C ATOM 237 CB THR A 47 35.849 36.568 27.265 1.00 28.37 A C ATOM 238 OG1 THR A 47 35.055 35.513 27.822 1.00 28.12 A O ATOM 239 CG2 THR A 47 35.130 37.169 26.071 1.00 28.11 A C ATOM 240 C THR A 47 38.097 35.897 28.088 1.00 25.47 A C ATOM 241 O THR A 47 38.111 34.862 28.759 1.00 24.25 A O ATOM 242 N TYR A 48 38.820 36.973 28.382 1.00 24.41 A N ATOM 243 CA TYR A 48 39.716 37.010 29.526 1.00 24.02 A C ATOM 244 CB TYR A 48 41.142 36.566 29.126 1.00 23.01 A C ATOM 245 CG TYR A 48 41.265 35.192 28.492 1.00 22.29 A C ATOM 246 CD1 TYR A 48 40.966 34.992 27.143 1.00 21.16 A C ATOM 247 CE1 TYR A 48 41.035 33.713 26.568 1.00 20.20 A C ATOM 248 CD2 TYR A 48 41.647 34.079 29.254 1.00 21.34 A C ATOM 249 CE2 TYR A 48 41.721 32.806 28.688 1.00 20.29 A C ATOM 250 CZ TYR A 48 41.409 32.633 27.348 1.00 19.58 A C ATOM 251 OH TYR A 48 41.436 31.378 26.795 1.00 20.11 A O ATOM 252 C TYR A 48 39.829 38.419 30.085 1.00 24.38 A C ATOM 253 O TYR A 48 39.512 39.403 29.409 1.00 22.46 A O ATOM 254 N THR A 49 40.288 38.497 31.329 1.00 24.50 A N ATOM 255 CA THR A 49 40.554 39.774 31.974 1.00 25.25 A C ATOM 256 CB THR A 49 40.510 39.647 33.515 1.00 26.57 A C ATOM 257 OG1 THR A 49 41.215 38.459 33.914 1.00 26.24 A O ATOM 258 CG2 THR A 49 39.056 39.580 34.017 1.00 24.91 A C ATOM 259 C THR A 49 42.000 40.027 31.524 1.00 25.63 A C ATOM 260 O THR A 49 42.738 39.079 31.248 1.00 24.71 A O ATOM 261 N MET A 50 42.414 41.281 31.424 1.00 26.39 A N ATOM 262 CA MET A 50 43.776 41.545 30.986 1.00 26.62 A C ATOM 263 CB MET A 50 44.053 43.040 30.977 1.00 25.74 A C ATOM 264 CG MET A 50 43.446 43.740 29.780 1.00 25.74 A C ATOM 265 SD MET A 50 44.280 43.286 28.239 1.00 24.59 A S ATOM 266 CE MET A 50 45.652 44.433 28.225 1.00 22.52 A C ATOM 267 C MET A 50 44.797 40.832 31.855 1.00 28.23 A C ATOM 268 O MET A 50 45.890 40.518 31.396 1.00 29.67 A O ATOM 269 N LYS A 51 44.442 40.554 33.105 1.00 28.66 A N ATOM 270 CA LYS A 51 45.370 39.872 33.993 1.00 29.11 A C ATOM 271 CB LYS A 51 44.878 39.943 35.439 1.00 32.66 A C ATOM 272 CG LYS A 51 45.919 39.458 36.443 1.00 37.67 A C ATOM 273 CD LYS A 51 45.462 39.604 37.889 1.00 41.07 A C ATOM 274 CE LYS A 51 46.527 39.071 38.855 1.00 42.73 A C ATOM 275 NZ LYS A 51 46.109 39.129 40.295 1.00 45.66 A N ATOM 276 C LYS A 51 45.597 38.411 33.586 1.00 28.29 A C ATOM 277 O LYS A 51 46.723 37.908 33.669 1.00 28.36 A O ATOM 278 N GLU A 52 44.537 37.729 33.152 1.00 25.71 A N ATOM 279 CA GLU A 52 44.662 36.334 32.732 1.00 23.60 A C ATOM 280 CB GLU A 52 43.278 35.702 32.522 1.00 24.83 A C ATOM 281 CG GLU A 52 42.420 35.589 33.777 1.00 27.15 A C ATOM 282 CD GLU A 52 40.989 35.116 33.479 1.00 29.01 A C ATOM 283 OE1 GLU A 52 40.281 35.785 32.691 1.00 29.80 A O ATOM 284 OE2 GLU A 52 40.568 34.078 34.032 1.00 29.19 A O ATOM 285 C GLU A 52 45.476 36.230 31.432 1.00 21.67 A C ATOM 286 O GLU A 52 46.128 35.214 31.183 1.00 20.99 A O ATOM 287 N VAL A 53 45.425 37.266 30.598 1.00 18.55 A N ATOM 288 CA VAL A 53 46.181 37.255 29.351 1.00 16.46 A C ATOM 289 CB VAL A 53 45.807 38.454 28.423 1.00 17.02 A C ATOM 290 CG1 VAL A 53 46.806 38.553 27.264 1.00 15.92 A C ATOM 291 CG2 VAL A 53 44.402 38.261 27.853 1.00 14.61 A C ATOM 292 C VAL A 53 47.650 37.331 29.742 1.00 15.15 A C ATOM 293 O VAL A 53 48.436 36.443 29.403 1.00 13.10 A O ATOM 294 N LEU A 54 48.010 38.394 30.463 1.00 15.42 A N ATOM 295 CA LEU A 54 49.375 38.570 30.952 1.00 14.74 A C ATOM 296 CB LEU A 54 49.454 39.698 31.982 1.00 12.86 A C ATOM 297 CG LEU A 54 49.718 41.124 31.497 1.00 13.00 A C ATOM 298 CD1 LEU A 54 50.874 41.100 30.500 1.00 14.60 A C ATOM 299 CD2 LEU A 54 48.494 41.706 30.859 1.00 11.73 A C ATOM 300 C LEU A 54 49.846 37.281 31.619 1.00 15.13 A C ATOM 301 O LEU A 54 51.009 36.897 31.502 1.00 16.88 A O ATOM 302 N PHE A 55 48.942 36.605 32.312 1.00 14.69 A N ATOM 303 CA PHE A 55 49.305 35.371 32.991 1.00 16.41 A C ATOM 304 CB PHE A 55 48.137 34.831 33.819 1.00 18.34 A C ATOM 305 CG PHE A 55 48.428 33.500 34.429 1.00 20.72 A C ATOM 306 CD1 PHE A 55 49.136 33.411 35.626 1.00 20.24 A C ATOM 307 CD2 PHE A 55 48.101 32.324 33.749 1.00 20.52 A C ATOM 308 CE1 PHE A 55 49.524 32.170 36.135 1.00 20.60 A C ATOM 309 CE2 PHE A 55 48.485 31.079 34.248 1.00 21.73 A C ATOM 310 CZ PHE A 55 49.199 31.001 35.444 1.00 20.59 A C ATOM 311 C PHE A 55 49.779 34.268 32.058 1.00 16.04 A C ATOM 312 O PHE A 55 50.853 33.698 32.259 1.00 17.31 A O ATOM 313 N TYR A 56 48.960 33.949 31.060 1.00 16.71 A N ATOM 314 CA TYR A 56 49.283 32.904 30.087 1.00 17.61 A C ATOM 315 CB TYR A 56 48.079 32.620 29.189 1.00 18.45 A C ATOM 316 CG TYR A 56 46.996 31.859 29.902 1.00 21.48 A C ATOM 317 CD1 TYR A 56 47.213 30.541 30.318 1.00 23.38 A C ATOM 318 CE1 TYR A 56 46.237 29.832 31.013 1.00 25.16 A C ATOM 319 CD2 TYR A 56 45.766 32.459 30.198 1.00 22.53 A C ATOM 320 CE2 TYR A 56 44.773 31.761 30.898 1.00 23.90 A C ATOM 321 CZ TYR A 56 45.019 30.445 31.303 1.00 26.15 A C ATOM 322 OH TYR A 56 44.065 29.738 32.003 1.00 26.91 A O ATOM 323 C TYR A 56 50.450 33.345 29.243 1.00 16.78 A C ATOM 324 O TYR A 56 51.235 32.530 28.754 1.00 18.53 A O ATOM 325 N LEU A 57 50.543 34.656 29.065 1.00 15.78 A N ATOM 326 CA LEU A 57 51.619 35.252 28.300 1.00 13.13 A C ATOM 327 CB LEU A 57 51.348 36.749 28.171 1.00 11.95 A C ATOM 328 CG LEU A 57 51.232 37.364 26.771 1.00 13.21 A C ATOM 329 CD1 LEU A 57 50.535 36.422 25.805 1.00 10.11 A C ATOM 330 CD2 LEU A 57 50.491 38.694 26.888 1.00 10.01 A C ATOM 331 C LEU A 57 52.922 34.973 29.074 1.00 12.23 A C ATOM 332 O LEU A 57 53.974 34.734 28.477 1.00 9.19 A O ATOM 333 N GLY A 58 52.824 34.984 30.404 1.00 11.88 A N ATOM 334 CA GLY A 58 53.969 34.719 31.249 1.00 14.46 A C ATOM 335 C GLY A 58 54.403 33.278 31.089 1.00 17.50 A C ATOM 336 O GLY A 58 55.594 32.988 30.928 1.00 18.69 A O ATOM 337 N GLN A 59 53.435 32.368 31.132 1.00 18.46 A N ATOM 338 CA GLN A 59 53.728 30.958 30.975 1.00 19.45 A C ATOM 339 CB GLN A 59 52.463 30.128 31.161 1.00 22.28 A C ATOM 340 CG GLN A 59 51.877 30.260 32.549 1.00 24.82 A C ATOM 341 CD GLN A 59 52.956 30.214 33.619 1.00 25.90 A C ATOM 342 OE1 GLN A 59 53.655 29.212 33.768 1.00 26.11 A O ATOM 343 NE2 GLN A 59 53.104 31.312 34.361 1.00 26.90 A N ATOM 344 C GLN A 59 54.299 30.729 29.592 1.00 19.50 A C ATOM 345 O GLN A 59 55.218 29.927 29.410 1.00 20.93 A O ATOM 346 N TYR A 60 53.765 31.450 28.616 1.00 17.52 A N ATOM 347 CA TYR A 60 54.239 31.315 27.252 1.00 18.33 A C ATOM 348 CB TYR A 60 53.432 32.220 26.317 1.00 14.85 A C ATOM 349 CG TYR A 60 53.776 32.069 24.845 1.00 15.47 A C ATOM 350 CD1 TYR A 60 53.279 31.001 24.089 1.00 14.63 A C ATOM 351 CE1 TYR A 60 53.581 30.873 22.716 1.00 11.14 A C ATOM 352 CD2 TYR A 60 54.594 33.007 24.196 1.00 15.88 A C ATOM 353 CE2 TYR A 60 54.902 32.886 22.826 1.00 13.26 A C ATOM 354 CZ TYR A 60 54.391 31.818 22.096 1.00 12.81 A C ATOM 355 OH TYR A 60 54.678 31.716 20.748 1.00 10.53 A O ATOM 356 C TYR A 60 55.728 31.664 27.158 1.00 20.42 A C ATOM 357 O TYR A 60 56.557 30.793 26.871 1.00 19.39 A O ATOM 358 N ILE A 61 56.069 32.928 27.418 1.00 21.45 A N ATOM 359 CA ILE A 61 57.458 33.361 27.319 1.00 23.11 A C ATOM 360 CB ILE A 61 57.624 34.874 27.588 1.00 22.76 A C ATOM 361 CG2 ILE A 61 56.939 35.682 26.499 1.00 23.31 A C ATOM 362 CG1 ILE A 61 57.085 35.230 28.965 1.00 22.24 A C ATOM 363 CD1 ILE A 61 57.384 36.655 29.349 1.00 23.32 A C ATOM 364 C ILE A 61 58.410 32.604 28.235 1.00 25.11 A C ATOM 365 O ILE A 61 59.573 32.396 27.899 1.00 25.25 A O ATOM 366 N MET A 62 57.931 32.186 29.393 1.00 27.56 A N ATOM 367 CA MET A 62 58.797 31.452 30.293 1.00 30.23 A C ATOM 368 CB MET A 62 58.158 31.371 31.680 1.00 32.88 A C ATOM 369 CG MET A 62 59.042 30.734 32.738 1.00 34.56 A C ATOM 370 SD MET A 62 58.113 29.481 33.637 1.00 39.80 A S ATOM 371 CE MET A 62 58.272 28.115 32.471 1.00 35.55 A C ATOM 372 C MET A 62 59.064 30.043 29.737 1.00 31.22 A C ATOM 373 O MET A 62 60.218 29.656 29.513 1.00 30.54 A O ATOM 374 N THR A 63 57.997 29.291 29.483 1.00 31.07 A N ATOM 375 CA THR A 63 58.150 27.931 28.976 1.00 31.77 A C ATOM 376 CB THR A 63 56.775 27.264 28.687 1.00 30.74 A C ATOM 377 OG1 THR A 63 56.009 28.092 27.808 1.00 31.02 A O ATOM 378 CG2 THR A 63 56.004 27.044 29.982 1.00 31.19 A C ATOM 379 C THR A 63 59.023 27.823 27.724 1.00 32.00 A C ATOM 380 O THR A 63 59.890 26.947 27.645 1.00 33.74 A O ATOM 381 N LYS A 64 58.797 28.697 26.747 1.00 30.45 A N ATOM 382 CA LYS A 64 59.578 28.655 25.522 1.00 29.14 A C ATOM 383 CB LYS A 64 58.783 29.262 24.363 1.00 28.22 A C ATOM 384 CG LYS A 64 57.581 28.437 23.947 1.00 26.54 A C ATOM 385 CD LYS A 64 56.870 29.029 22.738 1.00 26.08 A C ATOM 386 CE LYS A 64 57.757 29.029 21.514 1.00 26.73 A C ATOM 387 NZ LYS A 64 57.043 29.526 20.308 1.00 26.87 A N ATOM 388 C LYS A 64 60.926 29.358 25.674 1.00 29.64 A C ATOM 389 O LYS A 64 61.640 29.574 24.695 1.00 28.68 A O ATOM 390 N ARG A 65 61.264 29.716 26.909 1.00 31.08 A N ATOM 391 CA ARG A 65 62.541 30.359 27.206 1.00 31.77 A C ATOM 392 CB ARG A 65 63.624 29.278 27.281 1.00 32.61 A C ATOM 393 CG ARG A 65 63.422 28.319 28.456 1.00 36.27 A C ATOM 394 CD ARG A 65 64.128 26.980 28.268 1.00 38.75 A C ATOM 395 NE ARG A 65 63.951 26.108 29.433 1.00 41.50 A N ATOM 396 CZ ARG A 65 64.107 24.782 29.425 1.00 43.14 A C ATOM 397 NH1 ARG A 65 64.444 24.144 28.308 1.00 43.25 A N ATOM 398 NH2 ARG A 65 63.923 24.087 30.540 1.00 41.34 A N ATOM 399 C ARG A 65 62.931 31.442 26.193 1.00 30.62 A C ATOM 400 O ARG A 65 63.990 31.365 25.562 1.00 31.11 A O ATOM 401 N LEU A 66 62.069 32.447 26.043 1.00 27.85 A N ATOM 402 CA LEU A 66 62.315 33.554 25.117 1.00 24.57 A C ATOM 403 CB LEU A 66 60.996 34.080 24.535 1.00 21.73 A C ATOM 404 CG LEU A 66 60.195 33.192 23.588 1.00 18.58 A C ATOM 405 CD1 LEU A 66 58.917 33.893 23.171 1.00 16.38 A C ATOM 406 CD2 LEU A 66 61.039 32.882 22.373 1.00 16.78 A C ATOM 407 C LEU A 66 63.023 34.696 25.829 1.00 24.06 A C ATOM 408 O LEU A 66 63.334 35.715 25.221 1.00 22.74 A O ATOM 409 N TYR A 67 63.255 34.535 27.127 1.00 25.28 A N ATOM 410 CA TYR A 67 63.931 35.569 27.900 1.00 26.02 A C ATOM 411 CB TYR A 67 63.406 35.580 29.344 1.00 26.69 A C ATOM 412 CG TYR A 67 63.546 34.267 30.069 1.00 26.95 A C ATOM 413 CD1 TYR A 67 64.668 34.000 30.850 1.00 27.52 A C ATOM 414 CE1 TYR A 67 64.836 32.770 31.469 1.00 27.15 A C ATOM 415 CD2 TYR A 67 62.587 33.269 29.928 1.00 26.57 A C ATOM 416 CE2 TYR A 67 62.742 32.031 30.544 1.00 27.84 A C ATOM 417 CZ TYR A 67 63.875 31.787 31.312 1.00 27.23 A C ATOM 418 OH TYR A 67 64.068 30.554 31.888 1.00 24.32 A O ATOM 419 C TYR A 67 65.443 35.347 27.857 1.00 26.40 A C ATOM 420 O TYR A 67 65.917 34.216 27.828 1.00 25.07 A O ATOM 421 N ASP A 68 66.194 36.440 27.837 1.00 28.69 A N ATOM 422 CA ASP A 68 67.645 36.365 27.764 1.00 31.43 A C ATOM 423 CB ASP A 68 68.222 37.737 27.411 1.00 31.86 A C ATOM 424 CG ASP A 68 69.688 37.666 27.043 1.00 31.50 A C ATOM 425 OD1 ASP A 68 69.997 37.105 25.972 1.00 29.47 A O ATOM 426 OD2 ASP A 68 70.526 38.154 27.833 1.00 33.11 A O ATOM 427 C ASP A 68 68.313 35.848 29.035 1.00 33.44 A C ATOM 428 O ASP A 68 67.871 36.128 30.152 1.00 33.12 A O ATOM 429 N GLU A 69 69.399 35.105 28.845 1.00 36.37 A N ATOM 430 CA GLU A 69 70.152 34.529 29.950 1.00 39.07 A C ATOM 431 CB GLU A 69 71.214 33.558 29.420 1.00 42.56 A C ATOM 432 CG GLU A 69 70.627 32.277 28.851 1.00 48.37 A C ATOM 433 CD GLU A 69 69.565 31.677 29.766 1.00 51.95 A C ATOM 434 OE1 GLU A 69 69.848 31.514 30.974 1.00 54.24 A O ATOM 435 OE2 GLU A 69 68.449 31.370 29.281 1.00 54.25 A O ATOM 436 C GLU A 69 70.810 35.566 30.837 1.00 38.35 A C ATOM 437 O GLU A 69 70.695 35.506 32.057 1.00 38.84 A O ATOM 438 N LYS A 70 71.504 36.519 30.235 1.00 38.42 A N ATOM 439 CA LYS A 70 72.162 37.542 31.030 1.00 38.82 A C ATOM 440 CB LYS A 70 73.285 38.187 30.210 1.00 41.21 A C ATOM 441 CG LYS A 70 74.320 37.148 29.776 1.00 43.81 A C ATOM 442 CD LYS A 70 75.539 37.743 29.092 1.00 46.99 A C ATOM 443 CE LYS A 70 76.504 36.632 28.674 1.00 47.44 A C ATOM 444 NZ LYS A 70 77.794 37.156 28.143 1.00 48.71 A N ATOM 445 C LYS A 70 71.121 38.554 31.494 1.00 37.27 A C ATOM 446 O LYS A 70 70.854 38.673 32.690 1.00 36.92 A O ATOM 447 N GLN A 71 70.512 39.262 30.551 1.00 35.72 A N ATOM 448 CA GLN A 71 69.476 40.228 30.893 1.00 33.41 A C ATOM 449 CB GLN A 71 69.478 41.365 29.878 1.00 34.05 A C ATOM 450 CG GLN A 71 70.781 42.116 29.818 1.00 35.15 A C ATOM 451 CD GLN A 71 70.728 43.264 28.839 1.00 36.85 A C ATOM 452 OE1 GLN A 71 70.697 43.062 27.621 1.00 37.63 A O ATOM 453 NE2 GLN A 71 70.701 44.482 29.364 1.00 38.20 A N ATOM 454 C GLN A 71 68.115 39.512 30.898 1.00 31.00 A C ATOM 455 O GLN A 71 67.412 39.466 29.883 1.00 31.06 A O ATOM 456 N GLN A 72 67.754 38.957 32.051 1.00 27.04 A N ATOM 457 CA GLN A 72 66.505 38.216 32.200 1.00 23.77 A C ATOM 458 CB GLN A 72 66.437 37.583 33.592 1.00 21.94 A C ATOM 459 CG GLN A 72 65.172 36.783 33.877 1.00 19.04 A C ATOM 460 CD GLN A 72 65.343 35.849 35.066 1.00 18.27 A C ATOM 461 OE1 GLN A 72 66.141 34.917 35.018 1.00 16.43 A O ATOM 462 NE2 GLN A 72 64.600 36.098 36.137 1.00 19.03 A N ATOM 463 C GLN A 72 65.231 39.003 31.936 1.00 21.79 A C ATOM 464 O GLN A 72 64.255 38.438 31.464 1.00 20.39 A O ATOM 465 N HIS A 73 65.234 40.300 32.226 1.00 21.17 A N ATOM 466 CA HIS A 73 64.039 41.103 32.004 1.00 19.46 A C ATOM 467 CB HIS A 73 64.143 42.440 32.738 1.00 19.40 A C ATOM 468 CG HIS A 73 65.242 43.328 32.244 1.00 21.41 A C ATOM 469 CD2 HIS A 73 66.560 43.376 32.556 1.00 21.24 A C ATOM 470 ND1 HIS A 73 65.029 44.339 31.331 1.00 22.42 A N ATOM 471 CE1 HIS A 73 66.167 44.972 31.104 1.00 21.05 A C ATOM 472 NE2 HIS A 73 67.111 44.406 31.836 1.00 21.25 A N ATOM 473 C HIS A 73 63.772 41.338 30.526 1.00 20.37 A C ATOM 474 O HIS A 73 62.667 41.747 30.156 1.00 19.89 A O ATOM 475 N ILE A 74 64.774 41.083 29.681 1.00 19.94 A N ATOM 476 CA ILE A 74 64.607 41.259 28.239 1.00 19.76 A C ATOM 477 CB ILE A 74 65.942 41.605 27.523 1.00 20.27 A C ATOM 478 CG2 ILE A 74 65.699 41.745 26.022 1.00 18.27 A C ATOM 479 CG1 ILE A 74 66.536 42.906 28.072 1.00 22.09 A C ATOM 480 CD1 ILE A 74 65.704 44.127 27.810 1.00 22.98 A C ATOM 481 C ILE A 74 64.060 39.970 27.611 1.00 19.56 A C ATOM 482 O ILE A 74 64.555 38.875 27.885 1.00 19.09 A O ATOM 483 N VAL A 75 63.045 40.115 26.764 1.00 17.84 A N ATOM 484 CA VAL A 75 62.429 38.982 26.087 1.00 16.49 A C ATOM 485 CB VAL A 75 60.918 38.928 26.388 1.00 14.74 A C ATOM 486 CG1 VAL A 75 60.245 37.892 25.529 1.00 13.12 A C ATOM 487 CG2 VAL A 75 60.707 38.602 27.852 1.00 15.39 A C ATOM 488 C VAL A 75 62.650 39.136 24.588 1.00 17.78 A C ATOM 489 O VAL A 75 62.249 40.140 23.995 1.00 17.51 A O ATOM 490 N TYR A 76 63.302 38.150 23.977 1.00 17.97 A N ATOM 491 CA TYR A 76 63.570 38.201 22.544 1.00 18.96 A C ATOM 492 CB TYR A 76 64.958 37.622 22.229 1.00 20.36 A C ATOM 493 CG TYR A 76 66.085 38.507 22.713 1.00 22.91 A C ATOM 494 CD1 TYR A 76 66.677 38.306 23.966 1.00 22.46 A C ATOM 495 CE1 TYR A 76 67.685 39.168 24.438 1.00 24.23 A C ATOM 496 CD2 TYR A 76 66.525 39.587 21.942 1.00 23.56 A C ATOM 497 CE2 TYR A 76 67.532 40.457 22.408 1.00 23.98 A C ATOM 498 CZ TYR A 76 68.102 40.242 23.653 1.00 23.95 A C ATOM 499 OH TYR A 76 69.065 41.112 24.120 1.00 24.89 A O ATOM 500 C TYR A 76 62.499 37.438 21.801 1.00 17.43 A C ATOM 501 O TYR A 76 62.277 36.273 22.074 1.00 18.57 A O ATOM 502 N CYS A 77 61.841 38.094 20.850 1.00 19.17 A N ATOM 503 CA CYS A 77 60.755 37.458 20.100 1.00 20.17 A C ATOM 504 CB CYS A 77 59.410 37.978 20.628 1.00 18.05 A C ATOM 505 SG CYS A 77 59.288 39.802 20.678 1.00 17.89 A S ATOM 506 C CYS A 77 60.792 37.612 18.575 1.00 20.92 A C ATOM 507 O CYS A 77 59.817 37.293 17.902 1.00 22.93 A O ATOM 508 N SER A 78 61.904 38.083 18.027 1.00 21.73 A N ATOM 509 CA SER A 78 62.002 38.261 16.582 1.00 23.67 A C ATOM 510 CB SER A 78 63.369 38.828 16.209 1.00 23.31 A C ATOM 511 OG SER A 78 64.394 38.058 16.804 1.00 24.57 A O ATOM 512 C SER A 78 61.754 36.978 15.791 1.00 24.32 A C ATOM 513 O SER A 78 61.341 37.039 14.632 1.00 24.57 A O ATOM 514 N ASN A 79 62.003 35.824 16.403 1.00 23.65 A N ATOM 515 CA ASN A 79 61.794 34.553 15.709 1.00 24.00 A C ATOM 516 CB ASN A 79 63.081 33.709 15.694 1.00 24.75 A C ATOM 517 CG ASN A 79 64.160 34.293 14.792 1.00 25.05 A C ATOM 518 OD1 ASN A 79 65.059 34.994 15.254 1.00 25.04 A O ATOM 519 ND2 ASN A 79 64.064 34.015 13.495 1.00 25.70 A N ATOM 520 C ASN A 79 60.668 33.742 16.343 1.00 23.53 A C ATOM 521 O ASN A 79 60.753 32.512 16.451 1.00 23.89 A O ATOM 522 N ASP A 80 59.612 34.437 16.747 1.00 21.43 A N ATOM 523 CA ASP A 80 58.472 33.797 17.381 1.00 20.47 A C ATOM 524 CB ASP A 80 58.658 33.789 18.907 1.00 20.36 A C ATOM 525 CG ASP A 80 57.567 33.022 19.626 1.00 20.02 A C ATOM 526 OD1 ASP A 80 57.870 31.966 20.215 1.00 20.17 A O ATOM 527 OD2 ASP A 80 56.404 33.469 19.597 1.00 20.97 A O ATOM 528 C ASP A 80 57.193 34.542 17.024 1.00 20.46 A C ATOM 529 O ASP A 80 57.218 35.752 16.742 1.00 20.32 A O ATOM 530 N LEU A 81 56.078 33.812 17.034 1.00 19.74 A N ATOM 531 CA LEU A 81 54.766 34.379 16.725 1.00 19.05 A C ATOM 532 CB LEU A 81 53.685 33.351 17.047 1.00 20.17 A C ATOM 533 CG LEU A 81 52.228 33.802 17.023 1.00 23.86 A C ATOM 534 CD1 LEU A 81 51.870 34.357 15.650 1.00 24.25 A C ATOM 535 CD2 LEU A 81 51.339 32.608 17.378 1.00 24.57 A C ATOM 536 C LEU A 81 54.537 35.657 17.539 1.00 17.50 A C ATOM 537 O LEU A 81 54.022 36.656 17.027 1.00 15.88 A O ATOM 538 N LEU A 82 54.948 35.604 18.805 1.00 14.87 A N ATOM 539 CA LEU A 82 54.821 36.718 19.734 1.00 12.91 A C ATOM 540 CB LEU A 82 55.545 36.376 21.049 1.00 11.35 A C ATOM 541 CG LEU A 82 55.603 37.457 22.138 1.00 10.75 A C ATOM 542 CD1 LEU A 82 54.187 37.899 22.505 1.00 10.31 A C ATOM 543 CD2 LEU A 82 56.344 36.922 23.354 1.00 9.38 A C ATOM 544 C LEU A 82 55.374 38.023 19.157 1.00 12.97 A C ATOM 545 O LEU A 82 54.738 39.083 19.263 1.00 9.83 A O ATOM 546 N GLY A 83 56.561 37.944 18.557 1.00 12.95 A N ATOM 547 CA GLY A 83 57.163 39.129 17.980 1.00 15.06 A C ATOM 548 C GLY A 83 56.238 39.761 16.951 1.00 16.77 A C ATOM 549 O GLY A 83 56.060 40.980 16.919 1.00 15.55 A O ATOM 550 N ASP A 84 55.635 38.924 16.112 1.00 18.65 A N ATOM 551 CA ASP A 84 54.742 39.412 15.078 1.00 21.41 A C ATOM 552 CB ASP A 84 54.347 38.272 14.141 1.00 25.41 A C ATOM 553 CG ASP A 84 55.547 37.604 13.507 1.00 28.55 A C ATOM 554 OD1 ASP A 84 56.489 38.335 13.100 1.00 27.94 A O ATOM 555 OD2 ASP A 84 55.539 36.354 13.412 1.00 30.30 A O ATOM 556 C ASP A 84 53.491 40.055 15.650 1.00 21.92 A C ATOM 557 O ASP A 84 53.065 41.104 15.173 1.00 22.99 A O ATOM 558 N LEU A 85 52.906 39.428 16.666 1.00 21.04 A N ATOM 559 CA LEU A 85 51.697 39.955 17.288 1.00 22.00 A C ATOM 560 CB LEU A 85 51.092 38.915 18.240 1.00 21.98 A C ATOM 561 CG LEU A 85 50.821 37.544 17.609 1.00 23.19 A C ATOM 562 CD1 LEU A 85 50.177 36.593 18.628 1.00 20.96 A C ATOM 563 CD2 LEU A 85 49.923 37.734 16.390 1.00 22.60 A C ATOM 564 C LEU A 85 51.979 41.258 18.039 1.00 21.67 A C ATOM 565 O LEU A 85 51.122 42.143 18.102 1.00 20.70 A O ATOM 566 N PHE A 86 53.182 41.376 18.597 1.00 21.86 A N ATOM 567 CA PHE A 86 53.565 42.579 19.338 1.00 20.91 A C ATOM 568 CB PHE A 86 54.531 42.224 20.470 1.00 19.44 A C ATOM 569 CG PHE A 86 53.852 41.763 21.741 1.00 16.86 A C ATOM 570 CD1 PHE A 86 52.508 41.381 21.742 1.00 15.83 A C ATOM 571 CD2 PHE A 86 54.564 41.710 22.936 1.00 14.83 A C ATOM 572 CE1 PHE A 86 51.878 40.952 22.914 1.00 14.04 A C ATOM 573 CE2 PHE A 86 53.949 41.281 24.119 1.00 18.00 A C ATOM 574 CZ PHE A 86 52.596 40.902 24.105 1.00 16.08 A C ATOM 575 C PHE A 86 54.211 43.604 18.416 1.00 22.21 A C ATOM 576 O PHE A 86 54.233 44.797 18.714 1.00 23.98 A O ATOM 577 N GLY A 87 54.728 43.140 17.284 1.00 22.25 A N ATOM 578 CA GLY A 87 55.360 44.055 16.356 1.00 20.93 A C ATOM 579 C GLY A 87 56.711 44.578 16.820 1.00 20.93 A C ATOM 580 O GLY A 87 57.055 45.731 16.534 1.00 22.00 A O ATOM 581 N VAL A 88 57.471 43.752 17.542 1.00 18.42 A N ATOM 582 CA VAL A 88 58.802 44.136 18.014 1.00 16.75 A C ATOM 583 CB VAL A 88 58.791 44.793 19.420 1.00 16.55 A C ATOM 584 CG1 VAL A 88 57.951 46.054 19.405 1.00 15.93 A C ATOM 585 CG2 VAL A 88 58.312 43.795 20.462 1.00 13.35 A C ATOM 586 C VAL A 88 59.695 42.911 18.100 1.00 16.74 A C ATOM 587 O VAL A 88 59.215 41.792 18.273 1.00 16.22 A O ATOM 588 N PRO A 89 61.013 43.114 17.978 1.00 16.36 A N ATOM 589 CD PRO A 89 61.636 44.398 17.606 1.00 17.10 A C ATOM 590 CA PRO A 89 62.013 42.042 18.040 1.00 16.05 A C ATOM 591 CB PRO A 89 63.221 42.659 17.344 1.00 15.83 A C ATOM 592 CG PRO A 89 63.124 44.096 17.747 1.00 18.07 A C ATOM 593 C PRO A 89 62.322 41.623 19.476 1.00 16.21 A C ATOM 594 O PRO A 89 62.832 40.522 19.715 1.00 15.73 A O ATOM 595 N SER A 90 62.009 42.505 20.425 1.00 15.13 A N ATOM 596 CA SER A 90 62.243 42.232 21.843 1.00 14.02 A C ATOM 597 CB SER A 90 63.738 42.128 22.130 1.00 12.56 A C ATOM 598 OG SER A 90 64.336 43.403 21.986 1.00 13.74 A O ATOM 599 C SER A 90 61.652 43.350 22.702 1.00 12.89 A C ATOM 600 O SER A 90 61.331 44.422 22.192 1.00 12.05 A O ATOM 601 N PHE A 91 61.517 43.091 24.001 1.00 11.19 A N ATOM 602 CA PHE A 91 60.972 44.069 24.926 1.00 11.45 A C ATOM 603 CB PHE A 91 59.439 44.173 24.759 1.00 10.33 A C ATOM 604 CG PHE A 91 58.705 42.895 25.039 1.00 8.05 A C ATOM 605 CD1 PHE A 91 58.263 42.598 26.325 1.00 7.52 A C ATOM 606 CD2 PHE A 91 58.496 41.961 24.024 1.00 7.09 A C ATOM 607 CE1 PHE A 91 57.620 41.373 26.605 1.00 7.90 A C ATOM 608 CE2 PHE A 91 57.859 40.739 24.287 1.00 7.31 A C ATOM 609 CZ PHE A 91 57.419 40.445 25.588 1.00 7.15 A C ATOM 610 C PHE A 91 61.327 43.737 26.373 1.00 13.35 A C ATOM 611 O PHE A 91 61.795 42.632 26.685 1.00 12.34 A O ATOM 612 N SER A 92 61.102 44.708 27.254 1.00 14.78 A N ATOM 613 CA SER A 92 61.398 44.547 28.667 1.00 16.74 A C ATOM 614 CB SER A 92 62.086 45.809 29.203 1.00 15.00 A C ATOM 615 OG SER A 92 62.293 45.719 30.607 1.00 15.51 A O ATOM 616 C SER A 92 60.148 44.254 29.499 1.00 18.09 A C ATOM 617 O SER A 92 59.156 44.978 29.422 1.00 17.05 A O ATOM 618 N VAL A 93 60.206 43.189 30.295 1.00 19.76 A N ATOM 619 CA VAL A 93 59.094 42.822 31.163 1.00 21.70 A C ATOM 620 CB VAL A 93 59.322 41.442 31.866 1.00 22.34 A C ATOM 621 CG1 VAL A 93 59.380 40.329 30.828 1.00 22.82 A C ATOM 622 CG2 VAL A 93 60.606 41.462 32.683 1.00 20.47 A C ATOM 623 C VAL A 93 58.891 43.884 32.239 1.00 22.48 A C ATOM 624 O VAL A 93 58.089 43.702 33.140 1.00 24.56 A O ATOM 625 N LYS A 94 59.618 44.991 32.146 1.00 24.37 A N ATOM 626 CA LYS A 94 59.494 46.078 33.121 1.00 26.51 A C ATOM 627 CB LYS A 94 60.873 46.623 33.515 1.00 27.71 A C ATOM 628 CG LYS A 94 61.581 45.888 34.659 1.00 30.96 A C ATOM 629 CD LYS A 94 62.965 46.516 34.914 1.00 33.87 A C ATOM 630 CE LYS A 94 63.695 45.915 36.127 1.00 35.49 A C ATOM 631 NZ LYS A 94 65.052 46.534 36.343 1.00 35.43 A N ATOM 632 C LYS A 94 58.655 47.232 32.579 1.00 26.44 A C ATOM 633 O LYS A 94 58.156 48.054 33.342 1.00 27.30 A O ATOM 634 N GLU A 95 58.522 47.305 31.259 1.00 25.84 A N ATOM 635 CA GLU A 95 57.747 48.361 30.620 1.00 25.31 A C ATOM 636 CB GLU A 95 58.317 48.651 29.231 1.00 26.45 A C ATOM 637 CG GLU A 95 59.798 49.016 29.200 1.00 28.64 A C ATOM 638 CD GLU A 95 60.081 50.452 29.615 1.00 30.17 A C ATOM 639 OE1 GLU A 95 59.138 51.277 29.622 1.00 31.51 A O ATOM 640 OE2 GLU A 95 61.257 50.759 29.917 1.00 28.42 A O ATOM 641 C GLU A 95 56.286 47.904 30.500 1.00 24.66 A C ATOM 642 O GLU A 95 55.776 47.667 29.398 1.00 22.08 A O ATOM 643 N HIS A 96 55.619 47.799 31.647 1.00 24.62 A N ATOM 644 CA HIS A 96 54.234 47.348 31.702 1.00 26.26 A C ATOM 645 CB HIS A 96 53.694 47.452 33.132 1.00 27.90 A C ATOM 646 CG HIS A 96 54.457 46.635 34.128 1.00 30.90 A C ATOM 647 CD2 HIS A 96 55.784 46.395 34.257 1.00 31.52 A C ATOM 648 ND1 HIS A 96 53.844 45.963 35.164 1.00 32.30 A N ATOM 649 CE1 HIS A 96 54.761 45.345 35.887 1.00 32.43 A C ATOM 650 NE2 HIS A 96 55.947 45.591 35.358 1.00 32.16 A N ATOM 651 C HIS A 96 53.279 48.052 30.747 1.00 26.13 A C ATOM 652 O HIS A 96 52.436 47.400 30.136 1.00 26.36 A O ATOM 653 N ARG A 97 53.403 49.370 30.618 1.00 25.66 A N ATOM 654 CA ARG A 97 52.522 50.123 29.728 1.00 25.19 A C ATOM 655 CB ARG A 97 52.708 51.639 29.953 1.00 25.74 A C ATOM 656 CG ARG A 97 51.909 52.562 29.031 1.00 24.90 A C ATOM 657 CD ARG A 97 50.440 52.148 28.919 1.00 27.96 A C ATOM 658 NE ARG A 97 49.677 52.294 30.157 1.00 29.51 A N ATOM 659 CZ ARG A 97 48.450 51.804 30.337 1.00 29.81 A C ATOM 660 NH1 ARG A 97 47.849 51.133 29.359 1.00 31.04 A N ATOM 661 NH2 ARG A 97 47.817 51.986 31.489 1.00 27.76 A N ATOM 662 C ARG A 97 52.758 49.745 28.262 1.00 24.39 A C ATOM 663 O ARG A 97 51.805 49.623 27.497 1.00 25.23 A O ATOM 664 N LYS A 98 54.010 49.547 27.865 1.00 23.55 A N ATOM 665 CA LYS A 98 54.288 49.166 26.480 1.00 23.84 A C ATOM 666 CB LYS A 98 55.800 49.167 26.195 1.00 25.86 A C ATOM 667 CG LYS A 98 56.406 50.558 26.039 1.00 29.53 A C ATOM 668 CD LYS A 98 57.892 50.512 25.693 1.00 31.47 A C ATOM 669 CE LYS A 98 58.519 51.909 25.794 1.00 33.99 A C ATOM 670 NZ LYS A 98 59.989 51.918 25.509 1.00 34.37 A N ATOM 671 C LYS A 98 53.708 47.779 26.170 1.00 23.22 A C ATOM 672 O LYS A 98 53.150 47.563 25.091 1.00 21.35 A O ATOM 673 N ILE A 99 53.844 46.846 27.115 1.00 21.20 A N ATOM 674 CA ILE A 99 53.323 45.496 26.938 1.00 20.16 A C ATOM 675 CB ILE A 99 53.723 44.584 28.130 1.00 18.26 A C ATOM 676 CG2 ILE A 99 52.911 43.290 28.108 1.00 16.58 A C ATOM 677 CG1 ILE A 99 55.227 44.283 28.063 1.00 16.19 A C ATOM 678 CD1 ILE A 99 55.764 43.539 29.255 1.00 12.79 A C ATOM 679 C ILE A 99 51.799 45.545 26.802 1.00 21.79 A C ATOM 680 O ILE A 99 51.217 44.909 25.919 1.00 21.34 A O ATOM 681 N TYR A 100 51.156 46.316 27.672 1.00 23.34 A N ATOM 682 CA TYR A 100 49.706 46.457 27.639 1.00 24.14 A C ATOM 683 CB TYR A 100 49.243 47.387 28.763 1.00 25.12 A C ATOM 684 CG TYR A 100 48.602 46.651 29.911 1.00 28.22 A C ATOM 685 CD1 TYR A 100 49.336 45.739 30.681 1.00 28.65 A C ATOM 686 CE1 TYR A 100 48.734 45.008 31.700 1.00 28.51 A C ATOM 687 CD2 TYR A 100 47.248 46.817 30.196 1.00 28.65 A C ATOM 688 CE2 TYR A 100 46.632 46.088 31.215 1.00 29.38 A C ATOM 689 CZ TYR A 100 47.380 45.187 31.957 1.00 29.62 A C ATOM 690 OH TYR A 100 46.766 44.450 32.938 1.00 31.04 A O ATOM 691 C TYR A 100 49.154 46.960 26.299 1.00 25.10 A C ATOM 692 O TYR A 100 48.138 46.446 25.812 1.00 25.32 A O ATOM 693 N THR A 101 49.798 47.956 25.693 1.00 23.58 A N ATOM 694 CA THR A 101 49.269 48.447 24.434 1.00 24.54 A C ATOM 695 CB THR A 101 49.683 49.926 24.162 1.00 25.48 A C ATOM 696 OG1 THR A 101 51.085 50.021 23.920 1.00 26.87 A O ATOM 697 CG2 THR A 101 49.330 50.786 25.361 1.00 27.33 A C ATOM 698 C THR A 101 49.627 47.539 23.259 1.00 23.52 A C ATOM 699 O THR A 101 49.034 47.642 22.188 1.00 24.28 A O ATOM 700 N MET A 102 50.585 46.636 23.450 1.00 22.80 A N ATOM 701 CA MET A 102 50.921 45.697 22.377 1.00 20.40 A C ATOM 702 CB MET A 102 52.321 45.109 22.567 1.00 15.37 A C ATOM 703 CG MET A 102 53.403 46.131 22.321 1.00 14.03 A C ATOM 704 SD MET A 102 55.075 45.483 22.349 1.00 11.93 A S ATOM 705 CE MET A 102 55.294 45.184 24.125 1.00 10.87 A C ATOM 706 C MET A 102 49.863 44.592 22.392 1.00 19.65 A C ATOM 707 O MET A 102 49.528 44.017 21.356 1.00 19.47 A O ATOM 708 N ILE A 103 49.338 44.319 23.580 1.00 18.90 A N ATOM 709 CA ILE A 103 48.300 43.321 23.764 1.00 21.34 A C ATOM 710 CB ILE A 103 48.131 42.966 25.273 1.00 20.40 A C ATOM 711 CG2 ILE A 103 46.835 42.185 25.497 1.00 19.03 A C ATOM 712 CG1 ILE A 103 49.339 42.156 25.750 1.00 19.84 A C ATOM 713 CD1 ILE A 103 49.457 42.046 27.259 1.00 18.82 A C ATOM 714 C ILE A 103 46.985 43.896 23.228 1.00 24.13 A C ATOM 715 O ILE A 103 46.189 43.185 22.612 1.00 24.18 A O ATOM 716 N TYR A 104 46.775 45.192 23.461 1.00 27.06 A N ATOM 717 CA TYR A 104 45.566 45.886 23.016 1.00 29.10 A C ATOM 718 CB TYR A 104 45.608 47.344 23.491 1.00 30.33 A C ATOM 719 CG TYR A 104 45.205 47.494 24.940 1.00 30.58 A C ATOM 720 CD1 TYR A 104 45.775 48.469 25.754 1.00 29.56 A C ATOM 721 CE1 TYR A 104 45.415 48.584 27.095 1.00 29.30 A C ATOM 722 CD2 TYR A 104 44.259 46.638 25.502 1.00 31.51 A C ATOM 723 CE2 TYR A 104 43.894 46.746 26.836 1.00 31.90 A C ATOM 724 CZ TYR A 104 44.476 47.718 27.625 1.00 30.22 A C ATOM 725 OH TYR A 104 44.113 47.801 28.947 1.00 32.03 A O ATOM 726 C TYR A 104 45.321 45.824 21.510 1.00 29.49 A C ATOM 727 O TYR A 104 44.173 45.769 21.067 1.00 30.07 A O ATOM 728 N ARG A 105 46.397 45.831 20.731 1.00 30.44 A N ATOM 729 CA ARG A 105 46.291 45.757 19.281 1.00 31.09 A C ATOM 730 CB ARG A 105 47.561 46.288 18.614 1.00 32.59 A C ATOM 731 CG ARG A 105 47.624 47.803 18.491 1.00 35.48 A C ATOM 732 CD ARG A 105 48.761 48.212 17.567 1.00 38.68 A C ATOM 733 NE ARG A 105 50.069 47.877 18.129 1.00 41.14 A N ATOM 734 CZ ARG A 105 50.806 48.712 18.859 1.00 42.11 A C ATOM 735 NH1 ARG A 105 50.368 49.942 19.117 1.00 41.27 A N ATOM 736 NH2 ARG A 105 51.984 48.317 19.333 1.00 42.61 A N ATOM 737 C ARG A 105 46.059 44.317 18.845 1.00 31.15 A C ATOM 738 O ARG A 105 45.919 44.040 17.649 1.00 30.58 A O ATOM 739 N ASN A 106 46.029 43.403 19.814 1.00 30.35 A N ATOM 740 CA ASN A 106 45.797 41.992 19.523 1.00 31.38 A C ATOM 741 CB ASN A 106 46.927 41.120 20.069 1.00 30.13 A C ATOM 742 CG ASN A 106 48.164 41.186 19.219 1.00 30.74 A C ATOM 743 OD1 ASN A 106 48.957 42.126 19.327 1.00 30.89 A O ATOM 744 ND2 ASN A 106 48.335 40.193 18.346 1.00 30.12 A N ATOM 745 C ASN A 106 44.480 41.497 20.087 1.00 32.04 A C ATOM 746 O ASN A 106 44.309 40.303 20.324 1.00 30.99 A O ATOM 747 N LEU A 107 43.543 42.409 20.297 1.00 34.74 A N ATOM 748 CA LEU A 107 42.257 42.009 20.834 1.00 39.45 A C ATOM 749 CB LEU A 107 42.392 41.716 22.335 1.00 39.46 A C ATOM 750 CG LEU A 107 43.091 42.738 23.238 1.00 38.61 A C ATOM 751 CD1 LEU A 107 42.333 44.055 23.242 1.00 38.52 A C ATOM 752 CD2 LEU A 107 43.181 42.176 24.647 1.00 37.16 A C ATOM 753 C LEU A 107 41.157 43.025 20.604 1.00 42.25 A C ATOM 754 O LEU A 107 41.327 43.993 19.859 1.00 42.75 A O ATOM 755 N VAL A 108 40.021 42.778 21.245 1.00 46.00 A N ATOM 756 CA VAL A 108 38.859 43.653 21.163 1.00 49.43 A C ATOM 757 CB VAL A 108 37.823 43.129 20.149 1.00 48.08 A C ATOM 758 CG1 VAL A 108 37.030 44.290 19.594 1.00 48.02 A C ATOM 759 CG2 VAL A 108 38.509 42.343 19.040 1.00 46.78 A C ATOM 760 C VAL A 108 38.216 43.671 22.555 1.00 53.19 A C ATOM 761 O VAL A 108 37.589 42.690 22.966 1.00 52.78 A O ATOM 762 N VAL A 109 38.386 44.778 23.280 1.00 57.34 A N ATOM 763 CA VAL A 109 37.829 44.921 24.630 1.00 61.10 A C ATOM 764 CB VAL A 109 38.035 46.351 25.191 1.00 61.46 A C ATOM 765 CG1 VAL A 109 37.715 46.367 26.683 1.00 61.63 A C ATOM 766 CG2 VAL A 109 39.458 46.830 24.928 1.00 62.28 A C ATOM 767 C VAL A 109 36.326 44.631 24.662 1.00 63.47 A C ATOM 768 O VAL A 109 35.527 45.410 24.131 1.00 63.73 A O ATOM 769 N VAL A 110 35.947 43.518 25.293 1.00 65.46 A N ATOM 770 CA VAL A 110 34.542 43.127 25.392 1.00 67.21 A C ATOM 771 CB VAL A 110 34.366 41.919 26.365 1.00 66.97 A C ATOM 772 CG1 VAL A 110 32.939 41.374 26.283 1.00 67.04 A C ATOM 773 CG2 VAL A 110 35.371 40.825 26.033 1.00 66.24 A C ATOM 774 C VAL A 110 33.697 44.309 25.898 1.00 69.20 A C ATOM 775 O VAL A 110 34.287 45.249 26.488 1.00 69.94 A O ATOM 776 OXT VAL A 110 32.456 44.284 25.705 1.00 70.58 A O ATOM 777 C1 CID A 1 55.200 42.184 33.980 1.00 21.13 INH1 C ATOM 778 C2 CID A 1 54.610 43.160 33.125 1.00 21.31 INH1 C ATOM 779 C3 CID A 1 53.194 43.197 32.974 1.00 21.72 INH1 C ATOM 780 C4 CID A 1 52.372 42.284 33.667 1.00 21.74 INH1 C ATOM 781 C5 CID A 1 52.953 41.311 34.515 1.00 21.42 INH1 C ATOM 782 C6 CID A 1 54.387 41.238 34.692 1.00 22.49 INH1 C ATOM 783 C7 CID A 1 55.092 40.168 35.590 1.00 23.66 INH1 C ATOM 784 C8 CID A 1 54.267 39.594 36.800 1.00 25.69 INH1 C ATOM 785 O1 CID A 1 54.677 38.706 37.544 1.00 29.01 INH1 O ATOM 786 O2 CID A 1 53.229 40.347 37.224 1.00 30.64 INH1 O ATOM 787 N1 CID A 1 55.591 39.038 34.674 1.00 19.99 INH1 N ATOM 788 C9 CID A 1 54.593 38.352 33.801 1.00 18.95 INH1 C ATOM 789 C10 CID A 1 54.631 38.684 32.289 1.00 18.04 INH1 C ATOM 790 C11 CID A 1 55.647 39.488 31.665 1.00 17.01 INH1 C ATOM 791 C12 CID A 1 55.614 39.775 30.286 1.00 16.97 INH1 C ATOM 792 C13 CID A 1 54.563 39.261 29.507 1.00 17.64 INH1 C ATOM 793 CL1 CID A 1 54.498 39.606 27.865 1.00 14.96 INH1 CL ATOM 794 C14 CID A 1 53.550 38.464 30.083 1.00 18.96 INH1 C ATOM 795 C15 CID A 1 53.586 38.180 31.458 1.00 17.55 INH1 C ATOM 796 C16 CID A 1 54.559 36.817 34.087 1.00 18.08 INH1 C ATOM 797 O3 CID A 1 53.499 36.278 34.423 1.00 18.82 INH1 O ATOM 798 N2 CID A 1 55.695 36.036 33.977 1.00 16.78 INH1 N ATOM 799 C17 CID A 1 57.002 36.408 33.618 1.00 17.03 INH1 C ATOM 800 C18 CID A 1 57.616 37.644 33.943 1.00 16.70 INH1 C ATOM 801 C19 CID A 1 56.972 38.734 34.754 1.00 19.45 INH1 C ATOM 802 O4 CID A 1 57.728 39.367 35.532 1.00 18.52 INH1 O ATOM 803 C20 CID A 1 58.948 37.897 33.495 1.00 17.26 INH1 C ATOM 804 C21 CID A 1 59.660 36.940 32.750 1.00 18.91 INH1 C ATOM 805 I1 CID A 1 61.599 37.431 32.161 1.00 19.64 INH1 I ATOM 806 C22 CID A 1 59.069 35.711 32.436 1.00 17.86 INH1 C ATOM 807 C23 CID A 1 57.742 35.435 32.859 1.00 17.23 INH1 C ATOM 808 CL2 CID A 1 52.462 44.354 31.946 1.00 20.99 INH1 CL ATOM 809 CL3 CID A 1 59.915 34.517 31.548 1.00 20.31 INH1 CL END

TABLE 3 Superimposed: trigonal and tetragonal crystal forms REMARK Superimposed on/xray1/hmdm2/PDB/M338437.pdb REMARK The 19 atoms have an RMS distance of 0.249 A REMARK RMS delta B = 6.724 A2 REMARK Estimated RMSD for 2 random proteins = 5.398 A REMARK Relative RMSD = 0.04621 REMARK Normalised RMSD (100) = 1.471 A REMARK coordinates from restrained individual B-factor refinement REMARK refinement resolution: 25-2.6 A REMARK starting r = 0.2563 free_r = 0.2787 REMARK final r = 0.2553 free_r = 0.2761 REMARK B rmsd for bonded mainchain atoms = 1.483 target = 1.5 REMARK B rmsd for bonded sidechain atoms = 1.740 target = 2.0 REMARK B rmsd for angle mainchain atoms = 2.593 target = 2.0 REMARK B rmsd for angle sidechain atoms = 2.780 target = 2.5 REMARK rweight = 0.1000 (with wa = 3.71696) REMARK target = mlf steps = 30 REMARK sg = P4(3)2(1)2 a = 54.3 b = 54.3 c = 83.3 alpha = 90 beta = 90 gamma = 90 REMARK parameter file 1: MSI_CNX_TOPPAR: protein_rep.param REMARK parameter file 2: ../cid.par REMARK molecular structure file: recycle.psf REMARK input coordinates: anneal_9.pdb REMARK reflection file = ../M876273_2_P43212.cv REMARK ncs = none REMARK B-correction resolution: 6.0-2.6 REMARK initial B-factor correction applied to fobs: REMARK B11 = −1.189 B22 = −1.189 B33 = 2.379 REMARK B12 = 0.000 B13 = 0.000 B23 = 0.000 REMARK B-factor correction applied to coordinate array B: −0.119 REMARK bulk solvent: (Mask) density level = 0.341945 e/A{circumflex over ( )}3, B-factor = 22.3925 A{circumflex over ( )}2 REMARK reflections with |Fobs|/sigma_F <0.0 rejected REMARK reflections with |Fobs| >10000 * rms(Fobs) rejected REMARK theoretical total number of refl. in resol. range: 4173 (100.0%) REMARK number of unobserved reflections (no entry or |F| = 0): 9 (0.2%) REMARK number of reflections rejected: 0 (0.0%) REMARK total number of reflections used: 4164 (99.8%) REMARK number of reflections in working set: 3737 (89.6%) REMARK number of reflections in test set: 427 (10.2%) REMARK FILENAME = “bindividual.pdb” REMARK Written by CNX VERSION: 2000.12 ATOM 1 C GLY A 16 48.607 19.990 25.187 1.00 68.15 A ATOM 2 O GLY A 16 48.239 21.106 24.797 1.00 68.22 A ATOM 3 N GLY A 16 47.838 17.646 24.774 1.00 67.11 A ATOM 4 CA GLY A 16 47.594 18.911 25.537 1.00 67.90 A ATOM 5 N SER A 17 49.889 19.652 25.332 1.00 67.05 A ATOM 6 CA SER A 17 50.986 20.568 25.025 1.00 64.73 A ATOM 7 CB SER A 17 51.581 21.155 26.312 1.00 65.01 A ATOM 8 OG SER A 17 50.639 21.978 26.989 1.00 63.84 A ATOM 9 C SER A 17 52.053 19.794 24.258 1.00 62.82 A ATOM 10 O SER A 17 52.921 20.382 23.611 1.00 62.75 A ATOM 11 N GLN A 18 51.970 18.468 24.343 1.00 60.52 A ATOM 12 CA GLN A 18 52.895 17.577 23.647 1.00 57.89 A ATOM 13 CB GLN A 18 52.794 16.161 24.210 1.00 57.50 A ATOM 14 CG GLN A 18 53.480 15.955 25.534 1.00 57.38 A ATOM 15 CD GLN A 18 53.377 14.514 25.999 1.00 58.16 A ATOM 16 OE1 GLN A 18 53.614 13.581 25.228 1.00 56.84 A ATOM 17 NE2 GLN A 18 53.027 14.327 27.268 1.00 58.44 A ATOM 18 C GLN A 18 52.532 17.529 22.169 1.00 55.87 A ATOM 19 O GLN A 18 53.378 17.267 21.312 1.00 55.83 A ATOM 20 N ILE A 19 51.256 17.781 21.889 1.00 52.87 A ATOM 21 CA ILE A 19 50.727 17.763 20.532 1.00 50.05 A ATOM 22 CB ILE A 19 49.408 16.940 20.476 1.00 48.06 A ATOM 23 CG2 ILE A 19 48.886 16.873 19.053 1.00 48.17 A ATOM 24 CG1 ILE A 19 49.638 15.526 21.020 1.00 45.44 A ATOM 25 CD1 ILE A 19 50.552 14.677 20.180 1.00 43.26 A ATOM 26 C ILE A 19 50.443 19.194 20.066 1.00 49.72 A ATOM 27 O ILE A 19 50.014 20.036 20.856 1.00 49.03 A ATOM 28 N PRO A 20 50.702 19.490 18.777 1.00 49.57 A ATOM 29 CD PRO A 20 51.486 18.667 17.841 1.00 49.58 A ATOM 30 CA PRO A 20 50.469 20.822 18.209 1.00 49.39 A ATOM 31 CB PRO A 20 51.058 20.705 16.808 1.00 48.67 A ATOM 32 CG PRO A 20 52.153 19.717 16.991 1.00 48.94 A ATOM 33 C PRO A 20 48.982 21.187 18.171 1.00 49.97 A ATOM 34 O PRO A 20 48.138 20.358 17.819 1.00 50.18 A ATOM 35 N ALA A 21 48.672 22.429 18.534 1.00 49.45 A ATOM 36 CA ALA A 21 47.296 22.913 18.540 1.00 49.81 A ATOM 37 CB ALA A 21 47.270 24.405 18.880 1.00 49.85 A ATOM 38 C ALA A 21 46.613 22.670 17.189 1.00 49.65 A ATOM 39 O ALA A 21 45.483 22.179 17.128 1.00 49.33 A ATOM 40 N SER A 22 47.302 23.022 16.107 1.00 48.76 A ATOM 41 CA SER A 22 46.753 22.830 14.774 1.00 47.75 A ATOM 42 CB SER A 22 47.823 23.134 13.721 1.00 47.15 A ATOM 43 OG SER A 22 49.001 22.382 13.964 1.00 48.43 A ATOM 44 C SER A 22 46.254 21.391 14.628 1.00 46.34 A ATOM 45 O SER A 22 45.195 21.143 14.045 1.00 45.89 A ATOM 46 N GLU A 23 47.012 20.445 15.172 1.00 44.68 A ATOM 47 CA GLU A 23 46.632 19.041 15.098 1.00 43.25 A ATOM 48 CB GLU A 23 47.804 18.149 15.472 1.00 42.16 A ATOM 49 CG GLU A 23 47.513 16.684 15.303 1.00 40.86 A ATOM 50 CD GLU A 23 48.777 15.866 15.250 1.00 40.82 A ATOM 51 OE1 GLU A 23 49.695 16.146 16.045 1.00 41.52 A ATOM 52 OE2 GLU A 23 48.856 14.942 14.418 1.00 41.56 A ATOM 53 C GLU A 23 45.453 18.760 16.013 1.00 42.01 A ATOM 54 O GLU A 23 44.505 18.087 15.625 1.00 42.32 A ATOM 55 N GLN A 24 45.512 19.278 17.229 1.00 41.29 A ATOM 56 CA GLN A 24 44.413 19.089 18.154 1.00 42.07 A ATOM 57 CB GLN A 24 44.666 19.872 19.450 1.00 41.13 A ATOM 58 CG GLN A 24 45.643 19.180 20.391 1.00 42.57 A ATOM 59 CD GLN A 24 45.950 19.981 21.650 1.00 43.91 A ATOM 60 OE1 GLN A 24 45.068 20.622 22.233 1.00 44.84 A ATOM 61 NE2 GLN A 24 47.205 19.931 22.085 1.00 43.17 A ATOM 62 C GLN A 24 43.140 19.589 17.475 1.00 43.32 A ATOM 63 O GLN A 24 42.035 19.139 17.790 1.00 43.40 A ATOM 64 N GLU A 25 43.310 20.505 16.521 1.00 44.62 A ATOM 65 CA GLU A 25 42.183 21.095 15.795 1.00 44.92 A ATOM 66 CB GLU A 25 42.507 22.543 15.406 1.00 48.33 A ATOM 67 CG GLU A 25 43.121 23.398 16.516 1.00 53.04 A ATOM 68 CD GLU A 25 42.283 23.449 17.787 1.00 55.79 A ATOM 69 OE1 GLU A 25 42.680 24.180 18.720 1.00 57.11 A ATOM 70 OE2 GLU A 25 41.236 22.766 17.864 1.00 57.84 A ATOM 71 C GLU A 25 41.731 20.336 14.541 1.00 42.75 A ATOM 72 O GLU A 25 40.616 20.547 14.059 1.00 42.62 A ATOM 73 N THR A 26 42.587 19.467 14.008 1.00 40.18 A ATOM 74 CA THR A 26 42.237 18.692 12.814 1.00 38.13 A ATOM 75 CB THR A 26 43.254 17.547 12.563 1.00 37.92 A ATOM 76 OG1 THR A 26 44.589 18.059 12.647 1.00 37.02 A ATOM 77 CG2 THR A 26 43.047 16.942 11.187 1.00 36.76 A ATOM 78 C THR A 26 40.847 18.074 12.983 1.00 36.79 A ATOM 79 O THR A 26 40.511 17.574 14.054 1.00 36.47 A ATOM 80 N LEU A 27 40.036 18.128 11.931 1.00 36.63 A ATOM 81 CA LEU A 27 38.686 17.559 11.973 1.00 35.77 A ATOM 82 CB LEU A 27 37.739 18.336 11.052 1.00 36.16 A ATOM 83 CG LEU A 27 36.264 18.393 11.488 1.00 38.05 A ATOM 84 CD1 LEU A 27 36.120 19.331 12.692 1.00 36.12 A ATOM 85 CD2 LEU A 27 35.394 18.895 10.328 1.00 38.41 A ATOM 86 C LEU A 27 38.796 16.110 11.505 1.00 34.52 A ATOM 87 O LEU A 27 39.467 15.818 10.513 1.00 33.72 A ATOM 88 N VAL A 28 38.135 15.204 12.218 1.00 33.53 A ATOM 89 CA VAL A 28 38.214 13.787 11.886 1.00 32.88 A ATOM 90 CB VAL A 28 39.207 13.071 12.850 1.00 32.86 A ATOM 91 CG1 VAL A 28 40.592 13.685 12.724 1.00 31.21 A ATOM 92 CG2 VAL A 28 38.726 13.204 14.292 1.00 33.40 A ATOM 93 C VAL A 28 36.876 13.044 11.919 1.00 31.29 A ATOM 94 O VAL A 28 35.910 13.501 12.527 1.00 30.99 A ATOM 95 N ARG A 29 36.841 11.897 11.248 1.00 29.80 A ATOM 96 CA ARG A 29 35.655 11.054 11.198 1.00 28.94 A ATOM 97 CB ARG A 29 35.174 10.876 9.762 1.00 33.14 A ATOM 98 CG ARG A 29 34.296 11.991 9.254 1.00 38.54 A ATOM 99 CD ARG A 29 34.036 11.830 7.767 1.00 43.39 A ATOM 100 NE ARG A 29 33.084 12.828 7.296 1.00 47.28 A ATOM 101 CZ ARG A 29 31.772 12.741 7.477 1.00 49.30 A ATOM 102 NH1 ARG A 29 31.257 11.691 8.110 1.00 49.75 A ATOM 103 NH2 ARG A 29 30.978 13.716 7.049 1.00 50.29 A ATOM 104 C ARG A 29 35.994 9.688 11.762 1.00 26.43 A ATOM 105 O ARG A 29 36.680 8.895 11.110 1.00 25.41 A ATOM 106 N PRO A 30 35.528 9.397 12.989 1.00 24.69 A ATOM 107 CD PRO A 30 34.749 10.285 13.869 1.00 23.43 A ATOM 108 CA PRO A 30 35.784 8.108 13.647 1.00 23.00 A ATOM 109 CB PRO A 30 35.223 8.308 15.053 1.00 21.72 A ATOM 110 CG PRO A 30 35.147 9.792 15.218 1.00 22.48 A ATOM 111 C PRO A 30 35.023 7.001 12.923 1.00 22.20 A ATOM 112 O PRO A 30 33.945 7.243 12.382 1.00 22.27 A ATOM 113 N LYS A 31 35.580 5.796 12.910 1.00 21.65 A ATOM 114 CA LYS A 31 34.909 4.658 12.286 1.00 19.51 A ATOM 115 CB LYS A 31 35.901 3.519 12.056 1.00 19.68 A ATOM 116 CG LYS A 31 37.058 3.899 11.150 1.00 20.82 A ATOM 117 CD LYS A 31 38.006 2.724 10.976 1.00 22.74 A ATOM 118 CE LYS A 31 39.161 3.040 10.019 1.00 20.68 A ATOM 119 NZ LYS A 31 40.000 1.818 9.826 1.00 21.75 A ATOM 120 C LYS A 31 33.795 4.225 13.249 1.00 18.36 A ATOM 121 O LYS A 31 33.793 4.605 14.422 1.00 17.38 A ATOM 122 N PRO A 32 32.848 3.406 12.774 1.00 17.15 A ATOM 123 CD PRO A 32 32.886 2.665 11.501 1.00 16.30 A ATOM 124 CA PRO A 32 31.729 2.939 13.595 1.00 16.70 A ATOM 125 CB PRO A 32 31.178 1.775 12.778 1.00 16.53 A ATOM 126 CG PRO A 32 31.463 2.200 11.378 1.00 16.35 A ATOM 127 C PRO A 32 32.023 2.548 15.048 1.00 16.73 A ATOM 128 O PRO A 32 31.343 3.014 15.967 1.00 17.12 A ATOM 129 N LEU A 33 33.016 1.692 15.264 1.00 14.62 A ATOM 130 CA LEU A 33 33.324 1.265 16.619 1.00 13.59 A ATOM 131 CB LEU A 33 34.332 0.110 16.594 1.00 15.36 A ATOM 132 CG LEU A 33 33.787 −1.301 16.896 1.00 13.91 A ATOM 133 CD1 LEU A 33 32.250 −1.320 16.992 1.00 13.51 A ATOM 134 CD2 LEU A 33 34.270 −2.239 15.822 1.00 8.87 A ATOM 135 C LEU A 33 33.800 2.397 17.516 1.00 13.14 A ATOM 136 O LEU A 33 33.281 2.560 18.608 1.00 12.37 A ATOM 137 N LEU A 34 34.786 3.176 17.082 1.00 14.58 A ATOM 138 CA LEU A 34 35.238 4.305 17.895 1.00 13.84 A ATOM 139 CB LEU A 34 36.430 5.015 17.246 1.00 13.73 A ATOM 140 CG LEU A 34 36.892 6.346 17.861 1.00 10.65 A ATOM 141 CD1 LEU A 34 37.437 6.120 19.247 1.00 9.38 A ATOM 142 CD2 LEU A 34 37.951 6.971 16.986 1.00 11.47 A ATOM 143 C LEU A 34 34.073 5.294 18.042 1.00 15.75 A ATOM 144 O LEU A 34 33.877 5.874 19.103 1.00 16.50 A ATOM 145 N LEU A 35 33.294 5.484 16.979 1.00 17.07 A ATOM 146 CA LEU A 35 32.152 6.395 17.046 1.00 18.94 A ATOM 147 CB LEU A 35 31.440 6.482 15.690 1.00 16.70 A ATOM 148 CG LEU A 35 30.311 7.514 15.602 1.00 14.51 A ATOM 149 CD1 LEU A 35 30.880 8.904 15.849 1.00 13.73 A ATOM 150 CD2 LEU A 35 29.646 7.453 14.237 1.00 13.01 A ATOM 151 C LEU A 35 31.151 5.968 18.136 1.00 20.66 A ATOM 152 O LEU A 35 30.494 6.823 18.742 1.00 21.36 A ATOM 153 N LYS A 36 31.039 4.661 18.385 1.00 20.77 A ATOM 154 CA LYS A 36 30.135 4.152 19.415 1.00 22.28 A ATOM 155 CB LYS A 36 29.938 2.637 19.298 1.00 23.62 A ATOM 156 CG LYS A 36 28.839 2.214 18.330 1.00 28.23 A ATOM 157 CD LYS A 36 28.007 1.043 18.889 1.00 30.56 A ATOM 158 CE LYS A 36 28.853 −0.202 19.171 1.00 32.43 A ATOM 159 NZ LYS A 36 28.037 −1.385 19.580 1.00 31.16 A ATOM 160 C LYS A 36 30.668 4.471 20.807 1.00 23.86 A ATOM 161 O LYS A 36 29.901 4.855 21.700 1.00 26.24 A ATOM 162 N LEU A 37 31.971 4.301 21.006 1.00 23.16 A ATOM 163 CA LEU A 37 32.558 4.608 22.308 1.00 24.32 A ATOM 164 CB LEU A 37 34.085 4.515 22.263 1.00 25.18 A ATOM 165 CG LEU A 37 34.708 3.137 22.100 1.00 27.89 A ATOM 166 CD1 LEU A 37 36.217 3.232 22.302 1.00 28.24 A ATOM 167 CD2 LEU A 37 34.095 2.198 23.119 1.00 28.07 A ATOM 168 C LEU A 37 32.179 6.027 22.725 1.00 23.05 A ATOM 169 O LEU A 37 31.758 6.268 23.854 1.00 20.34 A ATOM 170 N LEU A 38 32.338 6.956 21.788 1.00 23.36 A ATOM 171 CA LEU A 38 32.055 8.359 22.022 1.00 24.58 A ATOM 172 CB LEU A 38 32.493 9.198 20.819 1.00 21.20 A ATOM 173 CG LEU A 38 33.886 8.937 20.238 1.00 19.16 A ATOM 174 CD1 LEU A 38 34.126 9.914 19.106 1.00 16.77 A ATOM 175 CD2 LEU A 38 34.966 9.092 21.306 1.00 18.04 A ATOM 176 C LEU A 38 30.581 8.602 22.302 1.00 27.20 A ATOM 177 O LEU A 38 30.236 9.411 23.162 1.00 29.33 A ATOM 178 N LYS A 39 29.702 7.908 21.590 1.00 28.13 A ATOM 179 CA LYS A 39 28.283 8.119 21.815 1.00 29.30 A ATOM 180 CB LYS A 39 27.467 7.488 20.686 1.00 28.63 A ATOM 181 CG LYS A 39 27.777 8.127 19.347 1.00 28.78 A ATOM 182 CD LYS A 39 26.776 7.761 18.276 1.00 27.98 A ATOM 183 CE LYS A 39 27.154 8.415 16.960 1.00 26.89 A ATOM 184 NZ LYS A 39 26.074 8.260 15.959 1.00 27.11 A ATOM 185 C LYS A 39 27.840 7.587 23.169 1.00 30.33 A ATOM 186 O LYS A 39 26.931 8.141 23.789 1.00 31.74 A ATOM 187 N SER A 40 28.495 6.531 23.644 1.00 30.27 A ATOM 188 CA SER A 40 28.148 5.948 24.939 1.00 29.62 A ATOM 189 CB SER A 40 28.995 4.691 25.213 1.00 28.81 A ATOM 190 OG SER A 40 30.349 5.002 25.520 1.00 26.68 A ATOM 191 C SER A 40 28.340 6.960 26.073 1.00 29.48 A ATOM 192 O SER A 40 27.745 6.822 27.139 1.00 29.59 A ATOM 193 N VAL A 41 29.170 7.974 25.843 1.00 30.35 A ATOM 194 CA VAL A 41 29.432 9.002 26.854 1.00 30.76 A ATOM 195 CB VAL A 41 30.944 9.047 27.267 1.00 30.64 A ATOM 196 CG1 VAL A 41 31.298 7.826 28.115 1.00 29.00 A ATOM 197 CG2 VAL A 41 31.834 9.108 26.030 1.00 28.32 A ATOM 198 C VAL A 41 29.013 10.407 26.413 1.00 32.02 A ATOM 199 O VAL A 41 29.742 11.380 26.628 1.00 31.05 A ATOM 200 N GLY A 42 27.845 10.509 25.779 1.00 33.77 A ATOM 201 CA GLY A 42 27.355 11.811 25.360 1.00 36.14 A ATOM 202 C GLY A 42 27.488 12.202 23.901 1.00 38.10 A ATOM 203 O GLY A 42 26.516 12.669 23.310 1.00 40.02 A ATOM 204 N ALA A 43 28.675 12.035 23.318 1.00 38.97 A ATOM 205 CA ALA A 43 28.897 12.403 21.919 1.00 39.16 A ATOM 206 CB ALA A 43 30.124 11.678 21.370 1.00 38.86 A ATOM 207 C ALA A 43 27.678 12.101 21.054 1.00 39.94 A ATOM 208 O ALA A 43 26.968 11.120 21.284 1.00 40.04 A ATOM 209 N GLN A 44 27.435 12.952 20.061 1.00 41.54 A ATOM 210 CA GLN A 44 26.294 12.769 19.173 1.00 42.78 A ATOM 211 CB GLN A 44 25.018 13.232 19.881 1.00 45.11 A ATOM 212 CG GLN A 44 25.132 14.598 20.546 1.00 47.61 A ATOM 213 CD GLN A 44 24.026 14.838 21.568 1.00 49.56 A ATOM 214 OE1 GLN A 44 23.986 15.884 22.227 1.00 49.35 A ATOM 215 NE2 GLN A 44 23.124 13.866 21.708 1.00 49.08 A ATOM 216 C GLN A 44 26.434 13.470 17.821 1.00 42.23 A ATOM 217 O GLN A 44 25.520 14.171 17.375 1.00 42.70 A ATOM 218 N LYS A 45 27.585 13.271 17.180 1.00 40.15 A ATOM 219 CA LYS A 45 27.871 13.845 15.870 1.00 37.90 A ATOM 220 CB LYS A 45 28.802 15.050 15.980 1.00 39.62 A ATOM 221 CG LYS A 45 28.359 16.141 16.933 1.00 41.18 A ATOM 222 CD LYS A 45 29.197 17.399 16.713 1.00 42.96 A ATOM 223 CE LYS A 45 30.690 17.093 16.732 1.00 45.64 A ATOM 224 NZ LYS A 45 31.535 18.294 16.451 1.00 48.08 A ATOM 225 C LYS A 45 28.590 12.774 15.071 1.00 36.61 A ATOM 226 O LYS A 45 28.771 11.657 15.553 1.00 36.82 A ATOM 227 N ASP A 46 29.012 13.121 13.859 1.00 34.69 A ATOM 228 CA ASP A 46 29.736 12.187 13.006 1.00 33.64 A ATOM 229 CB ASP A 46 29.089 12.074 11.617 1.00 35.21 A ATOM 230 CG ASP A 46 27.726 11.403 11.652 1.00 36.60 A ATOM 231 OD1 ASP A 46 27.557 10.427 12.417 1.00 35.63 A ATOM 232 OD2 ASP A 46 26.830 11.846 10.899 1.00 36.79 A ATOM 233 C ASP A 46 31.174 12.651 12.830 1.00 32.32 A ATOM 234 O ASP A 46 32.071 11.843 12.578 1.00 33.06 A ATOM 235 N THR A 47 31.388 13.959 12.950 1.00 30.30 A ATOM 236 CA THR A 47 32.718 14.543 12.790 1.00 27.52 A ATOM 237 CB THR A 47 32.762 15.556 11.620 1.00 28.37 A ATOM 238 OG1 THR A 47 31.586 16.375 11.650 1.00 28.12 A ATOM 239 CG2 THR A 47 32.846 14.836 10.287 1.00 28.11 A ATOM 240 C THR A 47 33.138 15.254 14.059 1.00 25.47 A ATOM 241 O THR A 47 32.307 15.811 14.781 1.00 24.25 A ATOM 242 N TYR A 48 34.441 15.227 14.324 1.00 24.41 A ATOM 243 CA TYR A 48 34.997 15.844 15.517 1.00 24.02 A ATOM 244 CB TYR A 48 35.073 14.830 16.681 1.00 23.01 A ATOM 245 CG TYR A 48 33.769 14.162 17.077 1.00 22.29 A ATOM 246 CD1 TYR A 48 33.259 13.087 16.347 1.00 21.16 A ATOM 247 CE1 TYR A 48 32.030 12.499 16.685 1.00 20.20 A ATOM 248 CD2 TYR A 48 33.021 14.632 18.166 1.00 21.34 A ATOM 249 CE2 TYR A 48 31.801 14.050 18.510 1.00 20.29 A ATOM 250 CZ TYR A 48 31.312 12.990 17.762 1.00 19.58 A ATOM 251 OH TYR A 48 30.092 12.442 18.066 1.00 20.11 A ATOM 252 C TYR A 48 36.412 16.340 15.265 1.00 24.38 A ATOM 253 O TYR A 48 37.080 15.913 14.318 1.00 22.46 A ATOM 254 N THR A 49 36.855 17.245 16.130 1.00 24.50 A ATOM 255 CA THR A 49 38.221 17.744 16.092 1.00 25.25 A ATOM 256 CB THR A 49 38.333 19.134 16.762 1.00 26.57 A ATOM 257 OG1 THR A 49 37.583 19.131 17.989 1.00 26.24 A ATOM 258 CG2 THR A 49 37.796 20.235 15.829 1.00 24.91 A ATOM 259 C THR A 49 38.932 16.699 16.965 1.00 25.63 A ATOM 260 O THR A 49 38.307 16.088 17.833 1.00 24.71 A ATOM 261 N MET A 50 40.216 16.466 16.740 1.00 26.39 A ATOM 262 CA MET A 50 40.907 15.470 17.545 1.00 26.62 A ATOM 263 CB MET A 50 42.373 15.388 17.150 1.00 25.74 A ATOM 264 CG MET A 50 42.589 14.617 15.865 1.00 25.74 A ATOM 265 SD MET A 50 42.250 12.852 16.072 1.00 24.59 A ATOM 266 CE MET A 50 43.816 12.259 16.701 1.00 22.52 A ATOM 267 C MET A 50 40.785 15.760 19.031 1.00 28.23 A ATOM 268 O MET A 50 40.843 14.848 19.847 1.00 29.67 A ATOM 269 N LYS A 51 40.594 17.026 19.388 1.00 28.66 A ATOM 270 CA LYS A 51 40.467 17.377 20.794 1.00 29.11 A ATOM 271 CB LYS A 51 40.573 18.891 20.980 1.00 32.66 A ATOM 272 CG LYS A 51 40.687 19.300 22.445 1.00 37.67 A ATOM 273 CD LYS A 51 40.874 20.801 22.628 1.00 41.07 A ATOM 274 CE LYS A 51 40.948 21.164 24.116 1.00 42.73 A ATOM 275 NZ LYS A 51 41.069 22.639 24.365 1.00 45.66 A ATOM 276 C LYS A 51 39.159 16.862 21.406 1.00 28.29 A ATOM 277 O LYS A 51 39.143 16.411 22.557 1.00 28.36 A ATOM 278 N GLU A 52 38.064 16.929 20.647 1.00 25.71 A ATOM 279 CA GLU A 52 36.775 16.451 21.144 1.00 23.60 A ATOM 280 CB GLU A 52 35.638 16.866 20.199 1.00 24.83 A ATOM 281 CG GLU A 52 35.407 18.369 20.084 1.00 27.15 A ATOM 282 CD GLU A 52 34.383 18.732 18.998 1.00 29.01 A ATOM 283 OE1 GLU A 52 34.598 18.371 17.818 1.00 29.80 A ATOM 284 OE2 GLU A 52 33.364 19.380 19.320 1.00 29.19 A ATOM 285 C GLU A 52 36.785 14.921 21.293 1.00 21.67 A ATOM 286 O GLU A 52 36.069 14.370 22.132 1.00 20.99 A ATOM 287 N VAL A 53 37.578 14.235 20.473 1.00 18.55 A ATOM 288 CA VAL A 53 37.659 12.782 20.559 1.00 16.46 A ATOM 289 CB VAL A 53 38.461 12.163 19.371 1.00 17.02 A ATOM 290 CG1 VAL A 53 38.749 10.682 19.645 1.00 15.92 A ATOM 291 CG2 VAL A 53 37.659 12.282 18.075 1.00 14.61 A ATOM 292 C VAL A 53 38.350 12.471 21.879 1.00 15.15 A ATOM 293 O VAL A 53 37.788 11.784 22.735 1.00 13.10 A ATOM 294 N LEU A 54 39.570 12.988 22.037 1.00 15.42 A ATOM 295 CA LEU A 54 40.328 12.814 23.273 1.00 14.74 A ATOM 296 CB LEU A 54 41.548 13.736 23.309 1.00 12.86 A ATOM 297 CG LEU A 54 42.871 13.232 22.730 1.00 13.00 A ATOM 298 CD1 LEU A 54 43.132 11.821 23.250 1.00 14.60 A ATOM 299 CD2 LEU A 54 42.833 13.235 21.232 1.00 11.73 A ATOM 300 C LEU A 54 39.439 13.153 24.467 1.00 15.13 A ATOM 301 O LEU A 54 39.515 12.511 25.514 1.00 16.88 A ATOM 302 N PHE A 55 38.588 14.156 24.309 1.00 14.69 A ATOM 303 CA PHE A 55 37.710 14.556 25.397 1.00 16.41 A ATOM 304 CB PHE A 55 36.904 15.803 25.028 1.00 18.34 A ATOM 305 CG PHE A 55 35.899 16.171 26.069 1.00 20.72 A ATOM 306 CD1 PHE A 55 36.278 16.916 27.184 1.00 20.24 A ATOM 307 CD2 PHE A 55 34.596 15.672 26.001 1.00 20.52 A ATOM 308 CE1 PHE A 55 35.376 17.153 28.223 1.00 20.60 A ATOM 309 CE2 PHE A 55 33.687 15.901 27.034 1.00 21.73 A ATOM 310 CZ PHE A 55 34.078 16.644 28.149 1.00 20.59 A ATOM 311 C PHE A 55 36.739 13.473 25.838 1.00 16.04 A ATOM 312 O PHE A 55 36.661 13.148 27.025 1.00 17.31 A ATOM 313 N TYR A 56 35.978 12.941 24.886 1.00 16.71 A ATOM 314 CA TYR A 56 34.996 11.892 25.165 1.00 17.61 A ATOM 315 CB TYR A 56 34.136 11.624 23.930 1.00 18.45 A ATOM 316 CG TYR A 56 33.142 12.723 23.671 1.00 21.48 A ATOM 317 CD1 TYR A 56 32.090 12.951 24.565 1.00 23.38 A ATOM 318 CE1 TYR A 56 31.182 13.987 24.363 1.00 25.16 A ATOM 319 CD2 TYR A 56 33.266 13.562 22.557 1.00 22.53 A ATOM 320 CE2 TYR A 56 32.363 14.610 22.339 1.00 23.90 A ATOM 321 CZ TYR A 56 31.322 14.816 23.251 1.00 26.15 A ATOM 322 OH TYR A 56 30.425 15.846 23.068 1.00 26.91 A ATOM 323 C TYR A 56 35.709 10.628 25.567 1.00 16.78 A ATOM 324 O TYR A 56 35.189 9.810 26.329 1.00 18.53 A ATOM 325 N LEU A 57 36.910 10.472 25.028 1.00 15.78 A ATOM 326 CA LEU A 57 37.743 9.325 25.327 1.00 13.13 A ATOM 327 CB LEU A 57 38.982 9.382 24.437 1.00 11.95 A ATOM 328 CG LEU A 57 39.277 8.207 23.497 1.00 13.21 A ATOM 329 CD1 LEU A 57 38.000 7.628 22.913 1.00 10.11 A ATOM 330 CD2 LEU A 57 40.224 8.690 22.402 1.00 10.01 A ATOM 331 C LEU A 57 38.108 9.418 26.821 1.00 12.23 A ATOM 332 O LEU A 57 38.197 8.403 27.515 1.00 9.19 A ATOM 333 N GLY A 58 38.291 10.649 27.300 1.00 11.88 A ATOM 334 CA GLY A 58 38.620 10.877 28.691 1.00 14.46 A ATOM 335 C GLY A 58 37.448 10.490 29.567 1.00 17.50 A ATOM 336 O GLY A 58 37.613 9.800 30.579 1.00 18.69 A ATOM 337 N GLN A 59 36.257 10.934 29.178 1.00 18.46 A ATOM 338 CA GLN A 59 35.059 10.614 29.929 1.00 19.45 A ATOM 339 CB GLN A 59 33.850 11.322 29.328 1.00 22.28 A ATOM 340 CG GLN A 59 33.967 12.829 29.389 1.00 24.82 A ATOM 341 CD GLN A 59 34.506 13.295 30.732 1.00 25.90 A ATOM 342 OE1 GLN A 59 33.883 13.079 31.771 1.00 26.11 A ATOM 343 NE2 GLN A 59 35.679 13.928 30.714 1.00 26.90 A ATOM 344 C GLN A 59 34.850 9.115 29.898 1.00 19.50 A ATOM 345 O GLN A 59 34.441 8.511 30.893 1.00 20.93 A ATOM 346 N TYR A 60 35.148 8.510 28.757 1.00 17.52 A ATOM 347 CA TYR A 60 34.991 7.075 28.617 1.00 18.33 A ATOM 348 CB TYR A 60 35.359 6.636 27.198 1.00 14.85 A ATOM 349 CG TYR A 60 35.120 5.162 26.914 1.00 15.47 A ATOM 350 CD1 TYR A 60 33.838 4.676 26.632 1.00 14.63 A ATOM 351 CE1 TYR A 60 33.620 3.311 26.347 1.00 11.14 A ATOM 352 CD2 TYR A 60 36.184 4.247 26.913 1.00 15.88 A ATOM 353 CE2 TYR A 60 35.974 2.882 26.631 1.00 13.26 A ATOM 354 CZ TYR A 60 34.691 2.425 26.349 1.00 12.81 A ATOM 355 OH TYR A 60 34.494 1.089 26.052 1.00 10.53 A ATOM 356 C TYR A 60 35.862 6.332 29.635 1.00 20.42 A ATOM 357 O TYR A 60 35.339 5.672 30.541 1.00 19.39 A ATOM 358 N ILE A 61 37.184 6.453 29.501 1.00 21.45 A ATOM 359 CA ILE A 61 38.092 5.753 30.401 1.00 23.11 A ATOM 360 CB ILE A 61 39.576 5.969 30.026 1.00 22.76 A ATOM 361 CG2 ILE A 61 39.879 5.334 28.680 1.00 23.31 A ATOM 362 CG1 ILE A 61 39.913 7.453 30.028 1.00 22.24 A ATOM 363 CD1 ILE A 61 41.385 7.709 29.846 1.00 23.32 A ATOM 364 C ILE A 61 37.911 6.115 31.869 1.00 25.11 A ATOM 365 O ILE A 61 38.112 5.284 32.751 1.00 25.25 A ATOM 366 N MET A 62 37.531 7.350 32.145 1.00 27.56 A ATOM 367 CA MET A 62 37.335 7.737 33.527 1.00 30.23 A ATOM 368 CB MET A 62 37.237 9.260 33.632 1.00 32.88 A ATOM 369 CG MET A 62 37.161 9.783 35.056 1.00 34.56 A ATOM 370 SD MET A 62 35.808 10.961 35.203 1.00 39.80 A ATOM 371 CE MET A 62 34.440 9.803 35.399 1.00 35.55 A ATOM 372 C MET A 62 36.066 7.073 34.087 1.00 31.22 A ATOM 373 O MET A 62 36.118 6.340 35.083 1.00 30.54 A ATOM 374 N THR A 63 34.934 7.302 33.428 1.00 31.07 A ATOM 375 CA THR A 63 33.673 6.735 33.896 1.00 31.77 A ATOM 376 CB THR A 63 32.495 7.074 32.939 1.00 30.74 A ATOM 377 OG1 THR A 63 32.818 6.664 31.608 1.00 31.02 A ATOM 378 CG2 THR A 63 32.206 8.569 32.956 1.00 31.19 A ATOM 379 C THR A 63 33.710 5.221 34.115 1.00 32.00 A ATOM 380 O THR A 63 33.230 4.730 35.142 1.00 33.74 A ATOM 381 N LYS A 64 34.265 4.481 33.159 1.00 30.45 A ATOM 382 CA LYS A 64 34.331 3.035 33.288 1.00 29.14 A ATOM 383 CB LYS A 64 34.397 2.380 31.905 1.00 28.22 A ATOM 384 CG LYS A 64 33.121 2.523 31.099 1.00 26.54 A ATOM 385 CD LYS A 64 33.198 1.785 29.769 1.00 26.08 A ATOM 386 CE LYS A 64 33.343 0.293 29.967 1.00 26.73 A ATOM 387 NZ LYS A 64 33.332 −0.444 28.675 1.00 26.87 A ATOM 388 C LYS A 64 35.509 2.586 34.151 1.00 29.64 A ATOM 389 O LYS A 64 35.824 1.398 34.223 1.00 28.68 A ATOM 390 N ARG A 65 36.160 3.548 34.799 1.00 31.08 A ATOM 391 CA ARG A 65 37.279 3.259 35.691 1.00 31.77 A ATOM 392 CB ARG A 65 36.720 2.800 37.041 1.00 32.61 A ATOM 393 CG ARG A 65 35.955 3.907 37.771 1.00 36.27 A ATOM 394 CD ARG A 65 34.975 3.376 38.812 1.00 38.75 A ATOM 395 NE ARG A 65 34.298 4.465 39.521 1.00 41.50 A ATOM 396 CZ ARG A 65 33.149 4.343 40.190 1.00 43.14 A ATOM 397 NH1 ARG A 65 32.519 3.173 40.251 1.00 43.25 A ATOM 398 NH2 ARG A 65 32.622 5.396 40.799 1.00 41.34 A ATOM 399 C ARG A 65 38.254 2.216 35.131 1.00 30.62 A ATOM 400 O ARG A 65 38.488 1.173 35.750 1.00 31.11 A ATOM 401 N LEU A 66 38.817 2.505 33.958 1.00 27.85 A ATOM 402 CA LEU A 66 39.773 1.606 33.309 1.00 24.57 A ATOM 403 CB LEU A 66 39.657 1.699 31.781 1.00 21.73 A ATOM 404 CG LEU A 66 38.392 1.185 31.099 1.00 18.58 A ATOM 405 CD1 LEU A 66 38.477 1.413 29.603 1.00 16.38 A ATOM 406 CD2 LEU A 66 38.240 −0.289 31.393 1.00 16.78 A ATOM 407 C LEU A 66 41.195 1.960 33.712 1.00 24.06 A ATOM 408 O LEU A 66 42.146 1.312 33.286 1.00 22.74 A ATOM 409 N TYR A 67 41.343 3.008 34.515 1.00 25.28 A ATOM 410 CA TYR A 67 42.665 3.428 34.962 1.00 26.02 A ATOM 411 CB TYR A 67 42.703 4.953 35.146 1.00 26.69 A ATOM 412 CG TYR A 67 41.675 5.492 36.106 1.00 26.95 A ATOM 413 CD1 TYR A 67 41.983 5.673 37.452 1.00 27.52 A ATOM 414 CE1 TYR A 67 41.025 6.108 38.356 1.00 27.15 A ATOM 415 CD2 TYR A 67 40.378 5.764 35.683 1.00 26.57 A ATOM 416 CE2 TYR A 67 39.407 6.202 36.579 1.00 27.84 A ATOM 417 CZ TYR A 67 39.738 6.368 37.919 1.00 27.23 A ATOM 418 OH TYR A 67 38.780 6.753 38.826 1.00 24.32 A ATOM 419 C TYR A 67 43.032 2.700 36.256 1.00 26.40 A ATOM 420 O TYR A 67 42.178 2.422 37.091 1.00 25.07 A ATOM 421 N ASP A 68 44.311 2.381 36.403 1.00 28.69 A ATOM 422 CA ASP A 68 44.785 1.659 37.574 1.00 31.43 A ATOM 423 CB ASP A 68 46.199 1.130 37.326 1.00 31.86 A ATOM 424 CG ASP A 68 46.635 0.139 38.382 1.00 31.50 A ATOM 425 OD1 ASP A 68 46.072 −0.975 38.409 1.00 29.47 A ATOM 426 OD2 ASP A 68 47.524 0.482 39.192 1.00 33.11 A ATOM 427 C ASP A 68 44.770 2.474 38.864 1.00 33.44 A ATOM 428 O ASP A 68 45.033 3.679 38.866 1.00 33.12 A ATOM 429 N GLU A 69 44.477 1.789 39.966 1.00 36.37 A ATOM 430 CA GLU A 69 44.415 2.416 41.279 1.00 39.07 A ATOM 431 CB GLU A 69 43.852 1.432 42.311 1.00 42.56 A ATOM 432 CG GLU A 69 42.371 1.145 42.123 1.00 48.37 A ATOM 433 CD GLU A 69 41.564 2.420 41.901 1.00 51.95 A ATOM 434 OE1 GLU A 69 41.715 3.364 42.708 1.00 54.24 A ATOM 435 OE2 GLU A 69 40.782 2.480 40.921 1.00 54.25 A ATOM 436 C GLU A 69 45.750 2.946 41.759 1.00 38.35 A ATOM 437 O GLU A 69 45.845 4.084 42.207 1.00 38.84 A ATOM 438 N LYS A 70 46.788 2.128 41.672 1.00 38.42 A ATOM 439 CA LYS A 70 48.096 2.575 42.118 1.00 38.82 A ATOM 440 CB LYS A 70 48.982 1.360 42.412 1.00 41.21 A ATOM 441 CG LYS A 70 48.362 0.471 43.491 1.00 43.81 A ATOM 442 CD LYS A 70 49.261 −0.669 43.940 1.00 46.99 A ATOM 443 CE LYS A 70 48.551 −1.515 44.999 1.00 47.44 A ATOM 444 NZ LYS A 70 49.436 −2.552 45.599 1.00 48.71 A ATOM 445 C LYS A 70 48.694 3.493 41.058 1.00 37.27 A ATOM 446 O LYS A 70 48.890 4.684 41.300 1.00 36.92 A ATOM 447 N GLN A 71 48.958 2.950 39.876 1.00 35.72 A ATOM 448 CA GLN A 71 49.496 3.755 38.787 1.00 33.41 A ATOM 449 CB GLN A 71 50.372 2.888 37.891 1.00 34.05 A ATOM 450 CG GLN A 71 51.544 2.272 38.608 1.00 35.15 A ATOM 451 CD GLN A 71 52.414 1.462 37.678 1.00 36.85 A ATOM 452 OE1 GLN A 71 52.026 0.382 37.220 1.00 37.63 A ATOM 453 NE2 GLN A 71 53.596 1.983 37.377 1.00 38.20 A ATOM 454 C GLN A 71 48.326 4.349 37.986 1.00 31.00 A ATOM 455 O GLN A 71 47.855 3.759 37.007 1.00 31.06 A ATOM 456 N GLN A 72 47.865 5.521 38.411 1.00 27.04 A ATOM 457 CA GLN A 72 46.737 6.192 37.771 1.00 23.77 A ATOM 458 CB GLN A 72 46.355 7.443 38.567 1.00 21.94 A ATOM 459 CG GLN A 72 45.189 8.240 37.996 1.00 19.04 A ATOM 460 CD GLN A 72 44.592 9.192 39.022 1.00 18.27 A ATOM 461 OE1 GLN A 72 44.040 8.758 40.029 1.00 16.43 A ATOM 462 NE2 GLN A 72 44.704 10.491 38.773 1.00 19.03 A ATOM 463 C GLN A 72 46.926 6.558 36.307 1.00 21.79 A ATOM 464 O GLN A 72 45.965 6.558 35.552 1.00 20.39 A ATOM 465 N HIS A 73 48.155 6.859 35.899 1.00 21.17 A ATOM 466 CA HIS A 73 48.395 7.227 34.510 1.00 19.46 A ATOM 467 CB HIS A 73 49.768 7.880 34.355 1.00 19.40 A ATOM 468 CG HIS A 73 50.918 6.974 34.667 1.00 21.41 A ATOM 469 CD2 HIS A 73 51.514 6.660 35.843 1.00 21.24 A ATOM 470 ND1 HIS A 73 51.613 6.290 33.692 1.00 22.42 A ATOM 471 CE1 HIS A 73 52.588 5.596 34.254 1.00 21.05 A ATOM 472 NE2 HIS A 73 52.548 5.804 35.559 1.00 21.25 A ATOM 473 C HIS A 73 48.273 6.037 33.572 1.00 20.37 A ATOM 474 O HIS A 73 48.166 6.219 32.355 1.00 19.89 A ATOM 475 N ILE A 74 48.290 4.823 34.128 1.00 19.94 A ATOM 476 CA ILE A 74 48.158 3.618 33.310 1.00 19.76 A ATOM 477 CB ILE A 74 48.869 2.389 33.941 1.00 20.27 A ATOM 478 CG2 ILE A 74 48.667 1.165 33.052 1.00 18.27 A ATOM 479 CG1 ILE A 74 50.368 2.655 34.118 1.00 22.09 A ATOM 480 CD1 ILE A 74 51.121 2.838 32.833 1.00 22.98 A ATOM 481 C ILE A 74 46.676 3.261 33.133 1.00 19.56 A ATOM 482 O ILE A 74 45.911 3.245 34.099 1.00 19.09 A ATOM 483 N VAL A 75 46.287 2.968 31.895 1.00 17.84 A ATOM 484 CA VAL A 75 44.913 2.603 31.578 1.00 16.49 A ATOM 485 CB VAL A 75 44.335 3.551 30.508 1.00 14.74 A ATOM 486 CG1 VAL A 75 42.999 3.053 30.027 1.00 13.12 A ATOM 487 CG2 VAL A 75 44.189 4.941 31.092 1.00 15.39 A ATOM 488 C VAL A 75 44.901 1.172 31.058 1.00 17.78 A ATOM 489 O VAL A 75 45.568 0.858 30.070 1.00 17.51 A ATOM 490 N TYR A 76 44.155 0.300 31.731 1.00 17.97 A ATOM 491 CA TYR A 76 44.077 −1.098 31.319 1.00 18.96 A ATOM 492 CB TYR A 76 44.029 −2.024 32.544 1.00 20.36 A ATOM 493 CG TYR A 76 45.341 −2.070 33.294 1.00 22.91 A ATOM 494 CD1 TYR A 76 45.582 −1.227 34.385 1.00 22.46 A ATOM 495 CE1 TYR A 76 46.827 −1.231 35.044 1.00 24.23 A ATOM 496 CD2 TYR A 76 46.371 −2.920 32.878 1.00 23.56 A ATOM 497 CE2 TYR A 76 47.621 −2.929 33.530 1.00 23.98 A ATOM 498 CZ TYR A 76 47.840 −2.083 34.606 1.00 23.95 A ATOM 499 OH TYR A 76 49.073 −2.071 35.223 1.00 24.89 A ATOM 500 C TYR A 76 42.856 −1.303 30.454 1.00 17.43 A ATOM 501 O TYR A 76 41.753 −0.999 30.870 1.00 18.57 A ATOM 502 N CYS A 77 43.052 −1.833 29.250 1.00 19.17 A ATOM 503 CA CYS A 77 41.940 −2.034 28.318 1.00 20.17 A ATOM 504 CB CYS A 77 41.984 −0.939 27.242 1.00 18.05 A ATOM 505 SG CYS A 77 43.606 −0.777 26.414 1.00 17.89 A ATOM 506 C CYS A 77 41.853 −3.405 27.639 1.00 20.92 A ATOM 507 O CYS A 77 41.084 −3.577 26.698 1.00 22.93 A ATOM 508 N SER A 78 42.619 −4.379 28.110 1.00 21.73 A ATOM 509 CA SER A 78 42.590 −5.706 27.504 1.00 23.67 A ATOM 510 CB SER A 78 43.569 −6.636 28.216 1.00 23.31 A ATOM 511 OG SER A 78 43.353 −6.594 29.612 1.00 24.57 A ATOM 512 C SER A 78 41.202 −6.344 27.497 1.00 24.32 A ATOM 513 O SER A 78 40.917 −7.189 26.647 1.00 24.57 A ATOM 514 N ASN A 79 40.343 −5.949 28.432 1.00 23.65 A ATOM 515 CA ASN A 79 38.996 −6.517 28.492 1.00 24.00 A ATOM 516 CB ASN A 79 38.716 −7.139 29.872 1.00 24.75 A ATOM 517 CG ASN A 79 39.516 −8.411 30.120 1.00 25.05 A ATOM 518 OD1 ASN A 79 40.571 −8.380 30.753 1.00 25.04 A ATOM 519 ND2 ASN A 79 39.021 −9.534 29.608 1.00 25.70 A ATOM 520 C ASN A 79 37.928 −5.472 28.186 1.00 23.53 A ATOM 521 O ASN A 79 36.857 −5.455 28.806 1.00 23.89 A ATOM 522 N ASP A 80 38.222 −4.611 27.219 1.00 21.43 A ATOM 523 CA ASP A 80 37.304 −3.554 26.831 1.00 20.47 A ATOM 524 CB ASP A 80 37.609 −2.277 27.631 1.00 20.36 A ATOM 525 CG ASP A 80 36.608 −1.170 27.370 1.00 20.02 A ATOM 526 OD1 ASP A 80 35.855 −0.817 28.299 1.00 20.17 A ATOM 527 OD2 ASP A 80 36.567 −0.656 26.236 1.00 20.97 A ATOM 528 C ASP A 80 37.439 −3.270 25.341 1.00 20.46 A ATOM 529 O ASP A 80 38.505 −3.492 24.744 1.00 20.32 A ATOM 530 N LEU A 81 36.350 −2.783 24.746 1.00 19.74 A ATOM 531 CA LEU A 81 36.317 −2.448 23.323 1.00 19.05 A ATOM 532 CB LEU A 81 35.019 −1.709 23.010 1.00 20.17 A ATOM 533 CG LEU A 81 34.870 −1.058 21.638 1.00 23.86 A ATOM 534 CD1 LEU A 81 35.022 −2.102 20.539 1.00 24.25 A ATOM 535 CD2 LEU A 81 33.500 −0.381 21.563 1.00 24.57 A ATOM 536 C LEU A 81 37.522 −1.576 22.957 1.00 17.50 A ATOM 537 O LEU A 81 38.155 −1.766 21.913 1.00 15.88 A ATOM 538 N LEU A 82 37.831 −0.633 23.846 1.00 14.87 A ATOM 539 CA LEU A 82 38.944 0.290 23.679 1.00 12.91 A ATOM 540 CB LEU A 82 39.117 1.125 24.961 1.00 11.35 A ATOM 541 CG LEU A 82 40.296 2.107 25.024 1.00 10.75 A ATOM 542 CD1 LEU A 82 40.216 3.088 23.855 1.00 10.31 A ATOM 543 CD2 LEU A 82 40.284 2.839 26.357 1.00 9.38 A ATOM 544 C LEU A 82 40.252 −0.430 23.344 1.00 12.97 A ATOM 545 O LEU A 82 40.992 −0.012 22.439 1.00 9.83 A ATOM 546 N GLY A 83 40.538 −1.503 24.080 1.00 12.95 A ATOM 547 CA GLY A 83 41.756 −2.248 23.834 1.00 15.06 A ATOM 548 C GLY A 83 41.816 −2.728 22.391 1.00 16.77 A ATOM 549 O GLY A 83 42.853 −2.635 21.732 1.00 15.55 A ATOM 550 N ASP A 84 40.691 −3.233 21.894 1.00 18.65 A ATOM 551 CA ASP A 84 40.631 −3.736 20.534 1.00 21.41 A ATOM 552 CB ASP A 84 39.294 −4.432 20.288 1.00 25.41 A ATOM 553 CG ASP A 84 39.043 −5.561 21.263 1.00 28.55 A ATOM 554 OD1 ASP A 84 40.004 −6.324 21.550 1.00 27.94 A ATOM 555 OD2 ASP A 84 37.887 −5.685 21.730 1.00 30.30 A ATOM 556 C ASP A 84 40.830 −2.640 19.503 1.00 21.92 A ATOM 557 O ASP A 84 41.547 −2.838 18.525 1.00 22.99 A ATOM 558 N LEU A 85 40.197 −1.491 19.719 1.00 21.04 A ATOM 559 CA LEU A 85 40.314 −0.373 18.790 1.00 22.00 A ATOM 560 CB LEU A 85 39.286 0.713 19.133 1.00 21.98 A ATOM 561 CG LEU A 85 37.835 0.226 19.211 1.00 23.19 A ATOM 562 CD1 LEU A 85 36.884 1.393 19.514 1.00 20.96 A ATOM 563 CD2 LEU A 85 37.472 −0.450 17.892 1.00 22.60 A ATOM 564 C LEU A 85 41.727 0.214 18.799 1.00 21.67 A ATOM 565 O LEU A 85 42.216 0.686 17.770 1.00 20.70 A ATOM 566 N PHE A 86 42.381 0.173 19.958 1.00 21.86 A ATOM 567 CA PHE A 86 43.740 0.702 20.086 1.00 20.91 A ATOM 568 CB PHE A 86 43.965 1.264 21.491 1.00 19.44 A ATOM 569 CG PHE A 86 43.487 2.688 21.671 1.00 16.86 A ATOM 570 CD1 PHE A 86 42.626 3.282 20.744 1.00 15.83 A ATOM 571 CD2 PHE A 86 43.899 3.431 22.773 1.00 14.83 A ATOM 572 CE1 PHE A 86 42.181 4.597 20.908 1.00 14.04 A ATOM 573 CE2 PHE A 86 43.461 4.749 22.955 1.00 18.00 A ATOM 574 CZ PHE A 86 42.597 5.334 22.013 1.00 16.08 A ATOM 575 C PHE A 86 44.774 −0.377 19.794 1.00 22.21 A ATOM 576 O PHE A 86 45.917 −0.080 19.447 1.00 23.98 A ATOM 577 N GLY A 87 44.370 −1.635 19.923 1.00 22.25 A ATOM 578 CA GLY A 87 45.298 −2.717 19.664 1.00 20.93 A ATOM 579 C GLY A 87 46.363 −2.894 20.735 1.00 20.93 A ATOM 580 O GLY A 87 47.499 −3.266 20.417 1.00 22.00 A ATOM 581 N VAL A 88 46.015 −2.621 21.994 1.00 18.42 A ATOM 582 CA VAL A 88 46.947 −2.787 23.110 1.00 16.75 A ATOM 583 CB VAL A 88 47.763 −1.506 23.426 1.00 16.55 A ATOM 584 CG1 VAL A 88 48.589 −1.098 22.223 1.00 15.93 A ATOM 585 CG2 VAL A 88 46.836 −0.394 23.892 1.00 13.35 A ATOM 586 C VAL A 88 46.185 −3.155 24.371 1.00 16.74 A ATOM 587 O VAL A 88 45.010 −2.822 24.518 1.00 16.22 A ATOM 588 N PRO A 89 46.854 −3.851 25.300 1.00 16.36 A ATOM 589 CD PRO A 89 48.202 −4.420 25.116 1.00 17.10 A ATOM 590 CA PRO A 89 46.269 −4.283 26.574 1.00 16.05 A ATOM 591 CB PRO A 89 47.181 −5.427 27.000 1.00 15.83 A ATOM 592 CG PRO A 89 48.517 −4.975 26.501 1.00 18.07 A ATOM 593 C PRO A 89 46.232 −3.155 27.604 1.00 16.21 A ATOM 594 O PRO A 89 45.462 −3.210 28.570 1.00 15.73 A ATOM 595 N SER A 90 47.066 −2.138 27.391 1.00 15.13 A ATOM 596 CA SER A 90 47.131 −0.988 28.292 1.00 14.02 A ATOM 597 CB SER A 90 47.652 −1.409 29.663 1.00 12.56 A ATOM 598 OG SER A 90 49.018 −1.764 29.560 1.00 13.74 A ATOM 599 C SER A 90 48.060 0.083 27.719 1.00 12.89 A ATOM 600 O SER A 90 48.833 −0.191 26.803 1.00 12.05 A ATOM 601 N PHE A 91 47.978 1.293 28.267 1.00 11.19 A ATOM 602 CA PHE A 91 48.807 2.397 27.816 1.00 11.45 A ATOM 603 CB PHE A 91 48.290 2.943 26.466 1.00 10.33 A ATOM 604 CG PHE A 91 46.891 3.480 26.518 1.00 8.05 A ATOM 605 CD1 PHE A 91 46.655 4.817 26.828 1.00 7.52 A ATOM 606 CD2 PHE A 91 45.800 2.638 26.304 1.00 7.09 A ATOM 607 CE1 PHE A 91 45.338 5.315 26.932 1.00 7.90 A ATOM 608 CE2 PHE A 91 44.485 3.118 26.404 1.00 7.31 A ATOM 609 CZ PHE A 91 44.256 4.467 26.721 1.00 7.15 A ATOM 610 C PHE A 91 48.869 3.517 28.852 1.00 13.35 A ATOM 611 O PHE A 91 48.090 3.547 29.817 1.00 12.34 A ATOM 612 N SER A 92 49.807 4.437 28.644 1.00 14.78 A ATOM 613 CA SER A 92 49.996 5.558 29.548 1.00 16.74 A ATOM 614 CB SER A 92 51.493 5.769 29.811 1.00 15.00 A ATOM 615 OG SER A 92 51.712 6.925 30.610 1.00 15.51 A ATOM 616 C SER A 92 49.384 6.854 29.012 1.00 18.09 A ATOM 617 O SER A 92 49.653 7.257 27.881 1.00 17.05 A ATOM 618 N VAL A 93 48.562 7.502 29.835 1.00 19.76 A ATOM 619 CA VAL A 93 47.941 8.765 29.456 1.00 21.70 A ATOM 620 CB VAL A 93 46.883 9.242 30.506 1.00 22.34 A ATOM 621 CG1 VAL A 93 45.727 8.253 30.571 1.00 22.82 A ATOM 622 CG2 VAL A 93 47.520 9.393 31.880 1.00 20.47 A ATOM 623 C VAL A 93 49.001 9.852 29.311 1.00 22.48 A ATOM 624 O VAL A 93 48.672 11.011 29.120 1.00 24.56 A ATOM 625 N LYS A 94 50.272 9.479 29.402 1.00 24.37 A ATOM 626 CA LYS A 94 51.369 10.441 29.268 1.00 26.51 A ATOM 627 CB LYS A 94 52.454 10.190 30.323 1.00 27.71 A ATOM 628 CG LYS A 94 52.235 10.866 31.682 1.00 30.96 A ATOM 629 CD LYS A 94 53.375 10.491 32.648 1.00 33.87 A ATOM 630 CE LYS A 94 53.298 11.223 33.998 1.00 35.49 A ATOM 631 NZ LYS A 94 54.414 10.825 34.930 1.00 35.43 A ATOM 632 C LYS A 94 52.014 10.375 27.886 1.00 26.44 A ATOM 633 O LYS A 94 52.693 11.309 27.469 1.00 27.30 A ATOM 634 N GLU A 95 51.821 9.260 27.190 1.00 25.84 A ATOM 635 CA GLU A 95 52.386 9.076 25.859 1.00 25.31 A ATOM 636 CB GLU A 95 52.648 7.590 25.612 1.00 26.45 A ATOM 637 CG GLU A 95 53.540 6.907 26.643 1.00 28.64 A ATOM 638 CD GLU A 95 55.022 7.198 26.457 1.00 30.17 A ATOM 639 OE1 GLU A 95 55.415 7.657 25.359 1.00 31.51 A ATOM 640 OE2 GLU A 95 55.798 6.948 27.407 1.00 28.42 A ATOM 641 C GLU A 95 51.394 9.612 24.818 1.00 24.66 A ATOM 642 O GLU A 95 50.809 8.851 24.037 1.00 22.08 A ATOM 643 N HIS A 96 51.225 10.932 24.808 1.00 24.62 A ATOM 644 CA HIS A 96 50.295 11.590 23.900 1.00 26.26 A ATOM 645 CB HIS A 96 50.410 13.113 24.027 1.00 27.90 A ATOM 646 CG HIS A 96 50.114 13.629 25.400 1.00 30.90 A ATOM 647 CD2 HIS A 96 50.422 13.138 26.625 1.00 31.52 A ATOM 648 ND1 HIS A 96 49.432 14.807 25.621 1.00 32.30 A ATOM 649 CE1 HIS A 96 49.333 15.018 26.922 1.00 32.43 A ATOM 650 NE2 HIS A 96 49.926 14.019 27.554 1.00 32.16 A ATOM 651 C HIS A 96 50.420 11.193 22.435 1.00 26.13 A ATOM 652 O HIS A 96 49.408 11.006 21.764 1.00 26.36 A ATOM 653 N ARG A 97 51.648 11.067 21.938 1.00 25.66 A ATOM 654 CA ARG A 97 51.857 10.696 20.540 1.00 25.19 A ATOM 655 CB ARG A 97 53.344 10.864 20.161 1.00 25.74 A ATOM 656 CG ARG A 97 53.734 10.433 18.746 1.00 24.90 A ATOM 657 CD ARG A 97 52.779 10.981 17.684 1.00 27.96 A ATOM 658 NE ARG A 97 52.817 12.435 17.532 1.00 29.51 A ATOM 659 CZ ARG A 97 51.931 13.132 16.820 1.00 29.81 A ATOM 660 NH1 ARG A 97 50.936 12.508 16.197 1.00 31.04 A ATOM 661 NH2 ARG A 97 52.037 14.451 16.722 1.00 27.76 A ATOM 662 C ARG A 97 51.371 9.269 20.265 1.00 24.39 A ATOM 663 O ARG A 97 50.775 9.012 19.222 1.00 25.23 A ATOM 664 N LYS A 98 51.605 8.344 21.189 1.00 23.55 A ATOM 665 CA LYS A 98 51.145 6.970 20.983 1.00 23.84 A ATOM 666 CB LYS A 98 51.678 6.034 22.082 1.00 25.86 A ATOM 667 CG LYS A 98 53.151 5.669 21.933 1.00 29.53 A ATOM 668 CD LYS A 98 53.621 4.689 23.004 1.00 31.47 A ATOM 669 CE LYS A 98 55.149 4.543 22.978 1.00 33.99 A ATOM 670 NZ LYS A 98 55.672 3.627 24.040 1.00 34.37 A ATOM 671 C LYS A 98 49.611 6.908 20.955 1.00 23.22 A ATOM 672 O LYS A 98 49.031 6.190 20.136 1.00 21.35 A ATOM 673 N ILE A 99 48.963 7.658 21.849 1.00 21.20 A ATOM 674 CA ILE A 99 47.507 7.689 21.909 1.00 20.16 A ATOM 675 CB ILE A 99 47.017 8.541 23.112 1.00 18.26 A ATOM 676 CG2 ILE A 99 45.526 8.843 22.980 1.00 16.58 A ATOM 677 CG1 ILE A 99 47.306 7.793 24.421 1.00 16.19 A ATOM 678 CD1 ILE A 99 47.022 8.589 25.665 1.00 12.79 A ATOM 679 C ILE A 99 46.949 8.256 20.601 1.00 21.79 A ATOM 680 O ILE A 99 46.008 7.710 20.019 1.00 21.34 A ATOM 681 N TYR A 100 47.543 9.348 20.133 1.00 23.34 A ATOM 682 CA TYR A 100 47.113 9.978 18.891 1.00 24.14 A ATOM 683 CB TYR A 100 47.961 11.220 18.611 1.00 25.12 A ATOM 684 CG TYR A 100 47.228 12.508 18.883 1.00 28.22 A ATOM 685 CD1 TYR A 100 46.799 12.833 20.177 1.00 28.65 A ATOM 686 CE1 TYR A 100 46.065 13.989 20.423 1.00 28.51 A ATOM 687 CD2 TYR A 100 46.908 13.379 17.843 1.00 28.65 A ATOM 688 CE2 TYR A 100 46.170 14.541 18.077 1.00 29.38 A ATOM 689 CZ TYR A 100 45.752 14.835 19.366 1.00 29.62 A ATOM 690 OH TYR A 100 45.002 15.961 19.589 1.00 31.04 A ATOM 691 C TYR A 100 47.149 9.048 17.671 1.00 25.10 A ATOM 692 O TYR A 100 46.216 9.055 16.857 1.00 25.32 A ATOM 693 N THR A 101 48.206 8.251 17.524 1.00 23.58 A ATOM 694 CA THR A 101 48.252 7.383 16.362 1.00 24.54 A ATOM 695 CB THR A 101 49.714 7.004 15.972 1.00 25.48 A ATOM 696 OG1 THR A 101 50.297 6.160 16.962 1.00 26.87 A ATOM 697 CG2 THR A 101 50.552 8.262 15.841 1.00 27.33 A ATOM 698 C THR A 101 47.376 6.143 16.527 1.00 23.52 A ATOM 699 O THR A 101 47.074 5.459 15.553 1.00 24.28 A ATOM 700 N MET A 102 46.949 5.851 17.753 1.00 22.80 A ATOM 701 CA MET A 102 46.052 4.711 17.956 1.00 20.40 A ATOM 702 CB MET A 102 46.081 4.229 19.408 1.00 15.37 A ATOM 703 CG MET A 102 47.385 3.556 19.756 1.00 14.03 A ATOM 704 SD MET A 102 47.437 2.805 21.384 1.00 11.93 A ATOM 705 CE MET A 102 47.530 4.281 22.436 1.00 10.87 A ATOM 706 C MET A 102 44.645 5.163 17.563 1.00 19.65 A ATOM 707 O MET A 102 43.829 4.371 17.091 1.00 19.47 A ATOM 708 N ILE A 103 44.384 6.451 17.755 1.00 18.90 A ATOM 709 CA ILE A 103 43.108 7.049 17.406 1.00 21.34 A ATOM 710 CB ILE A 103 42.959 8.459 18.055 1.00 20.40 A ATOM 711 CG2 ILE A 103 41.789 9.217 17.425 1.00 19.03 A ATOM 712 CG1 ILE A 103 42.757 8.312 19.565 1.00 19.84 A ATOM 713 CD1 ILE A 103 42.941 9.601 20.345 1.00 18.82 A ATOM 714 C ILE A 103 43.045 7.183 15.881 1.00 24.13 A ATOM 715 O ILE A 103 41.996 6.968 15.271 1.00 24.18 A ATOM 716 N TYR A 104 44.182 7.530 15.277 1.00 27.06 A ATOM 717 CA TYR A 104 44.283 7.701 13.827 1.00 29.10 A ATOM 718 CB TYR A 104 45.702 8.155 13.462 1.00 30.33 A ATOM 719 CG TYR A 104 45.914 9.635 13.689 1.00 30.58 A ATOM 720 CD1 TYR A 104 47.148 10.137 14.093 1.00 29.56 A ATOM 721 CE1 TYR A 104 47.328 11.499 14.323 1.00 29.30 A ATOM 722 CD2 TYR A 104 44.862 10.533 13.516 1.00 31.51 A ATOM 723 CE2 TYR A 104 45.032 11.892 13.742 1.00 31.90 A ATOM 724 CZ TYR A 104 46.264 12.366 14.146 1.00 30.22 A ATOM 725 OH TYR A 104 46.411 13.711 14.379 1.00 32.03 A ATOM 726 C TYR A 104 43.895 6.466 13.017 1.00 29.49 A ATOM 727 O TYR A 104 43.336 6.587 11.926 1.00 30.07 A ATOM 728 N ARG A 105 44.188 5.287 13.553 1.00 30.44 A ATOM 729 CA ARG A 105 43.851 4.039 12.883 1.00 31.09 A ATOM 730 CB ARG A 105 44.714 2.889 13.407 1.00 32.59 A ATOM 731 CG ARG A 105 46.098 2.802 12.783 1.00 35.48 A ATOM 732 CD ARG A 105 46.758 1.479 13.140 1.00 38.68 A ATOM 733 NE ARG A 105 47.041 1.380 14.572 1.00 41.14 A ATOM 734 CZ ARG A 105 48.198 1.727 15.132 1.00 42.11 A ATOM 735 NH1 ARG A 105 49.192 2.196 14.382 1.00 41.27 A ATOM 736 NH2 ARG A 105 48.362 1.605 16.446 1.00 42.61 A ATOM 737 C ARG A 105 42.382 3.705 13.104 1.00 31.15 A ATOM 738 O ARG A 105 41.887 2.692 12.599 1.00 30.58 A ATOM 739 N ASN A 106 41.691 4.552 13.867 1.00 30.35 A ATOM 740 CA ASN A 106 40.272 4.349 14.137 1.00 31.38 A ATOM 741 CB ASN A 106 39.995 4.297 15.639 1.00 30.13 A ATOM 742 CG ASN A 106 40.393 2.984 16.250 1.00 30.74 A ATOM 743 OD1 ASN A 106 41.568 2.754 16.549 1.00 30.89 A ATOM 744 ND2 ASN A 106 39.415 2.094 16.427 1.00 30.12 A ATOM 745 C ASN A 106 39.408 5.429 13.517 1.00 32.04 A ATOM 746 O ASN A 106 38.293 5.677 13.970 1.00 30.99 A ATOM 747 N LEU A 107 39.914 6.070 12.474 1.00 34.74 A ATOM 748 CA LEU A 107 39.144 7.115 11.828 1.00 39.45 A ATOM 749 CB LEU A 107 39.166 8.383 12.694 1.00 39.46 A ATOM 750 CG LEU A 107 40.507 8.908 13.220 1.00 38.61 A ATOM 751 CD1 LEU A 107 41.418 9.298 12.068 1.00 38.52 A ATOM 752 CD2 LEU A 107 40.252 10.105 14.120 1.00 37.16 A ATOM 753 C LEU A 107 39.614 7.441 10.425 1.00 42.25 A ATOM 754 O LEU A 107 40.442 6.732 9.848 1.00 42.75 A ATOM 755 N VAL A 108 39.057 8.516 9.882 1.00 46.00 A ATOM 756 CA VAL A 108 39.397 8.997 8.549 1.00 49.43 A ATOM 757 CB VAL A 108 38.365 8.541 7.499 1.00 48.08 A ATOM 758 CG1 VAL A 108 39.032 8.443 6.146 1.00 48.02 A ATOM 759 CG2 VAL A 108 37.735 7.216 7.907 1.00 46.78 A ATOM 760 C VAL A 108 39.389 10.529 8.612 1.00 53.19 A ATOM 761 O VAL A 108 38.321 11.145 8.684 1.00 52.78 A ATOM 762 N VAL A 109 40.576 11.136 8.601 1.00 57.34 A ATOM 763 CA VAL A 109 40.708 12.596 8.664 1.00 61.10 A ATOM 764 CB VAL A 109 42.177 13.052 8.480 1.00 61.46 A ATOM 765 CG1 VAL A 109 42.306 14.528 8.847 1.00 61.63 A ATOM 766 CG2 VAL A 109 43.115 12.193 9.320 1.00 62.28 A ATOM 767 C VAL A 109 39.875 13.293 7.584 1.00 63.47 A ATOM 768 O VAL A 109 40.196 13.206 6.394 1.00 63.73 A ATOM 769 N VAL A 110 38.817 13.989 8.004 1.00 65.46 A ATOM 770 CA VAL A 110 37.941 14.697 7.073 1.00 67.21 A ATOM 771 CB VAL A 110 36.927 15.603 7.840 1.00 66.97 A ATOM 772 CG1 VAL A 110 35.873 16.155 6.878 1.00 67.04 A ATOM 773 CG2 VAL A 110 36.262 14.817 8.961 1.00 66.24 A ATOM 774 C VAL A 110 38.775 15.570 6.119 1.00 69.20 A ATOM 775 O VAL A 110 39.949 15.862 6.458 1.00 69.94 A ATOM 776 OXT VAL A 110 38.248 15.956 5.046 1.00 70.58 A ATOM 777 C1 CID A 1 46.320 13.011 27.769 1.00 21.13 INH1 ATOM 778 C2 CID A 1 46.849 12.548 26.529 1.00 21.31 INH1 ATOM 779 C3 CID A 1 46.319 13.053 25.307 1.00 21.72 INH1 ATOM 780 C4 CID A 1 45.283 14.011 25.313 1.00 21.74 INH1 ATOM 781 C5 CID A 1 44.753 14.472 26.542 1.00 21.42 INH1 ATOM 782 C6 CID A 1 45.261 13.981 27.804 1.00 22.49 INH1 ATOM 783 C7 CID A 1 44.698 14.428 29.194 1.00 23.66 INH1 ATOM 784 C8 CID A 1 44.052 15.860 29.277 1.00 25.69 INH1 ATOM 785 O1 CID A 1 43.517 16.308 30.288 1.00 29.01 INH1 ATOM 786 O2 CID A 1 44.409 16.731 28.309 1.00 30.64 INH1 ATOM 787 N1 CID A 1 43.714 13.347 29.673 1.00 19.99 INH1 ATOM 788 C9 CID A 1 42.570 12.996 28.781 1.00 18.95 INH1 ATOM 789 C10 CID A 1 42.648 11.641 28.034 1.00 18.04 INH1 ATOM 790 C11 CID A 1 43.669 10.654 28.259 1.00 17.01 INH1 ATOM 791 C12 CID A 1 43.700 9.448 27.530 1.00 16.97 INH1 ATOM 792 C13 CID A 1 42.708 9.210 26.564 1.00 17.64 INH1 ATOM 793 CL1 CID A 1 42.737 7.786 25.674 1.00 14.96 INH1 ATOM 794 C14 CID A 1 41.687 10.153 26.318 1.00 18.96 INH1 ATOM 795 C15 CID A 1 41.659 11.354 27.046 1.00 17.55 INH1 ATOM 796 C16 CID A 1 41.205 13.214 29.506 1.00 18.08 INH1 ATOM 797 O3 CID A 1 40.363 13.973 29.015 1.00 18.82 INH1 ATOM 798 N2 CID A 1 40.909 12.577 30.698 1.00 16.78 INH1 ATOM 799 C17 CID A 1 41.690 11.680 31.447 1.00 17.03 INH1 ATOM 800 C18 CID A 1 43.101 11.735 31.572 1.00 16.70 INH1 ATOM 801 C19 CID A 1 43.977 12.786 30.947 1.00 19.45 INH1 ATOM 802 O4 CID A 1 44.965 13.160 31.626 1.00 18.52 INH1 ATOM 803 C20 CID A 1 43.769 10.744 32.353 1.00 17.26 INH1 ATOM 804 C21 CID A 1 43.051 9.726 33.006 1.00 18.91 INH1 ATOM 805 I1 CID A 1 44.145 8.343 34.119 1.00 19.64 INH1 ATOM 806 C22 CID A 1 41.657 9.670 32.902 1.00 17.86 INH1 ATOM 807 C23 CID A 1 40.966 10.637 32.123 1.00 17.23 INH1 ATOM 808 CL2 CID A 1 46.930 12.505 23.805 1.00 20.99 INH1 ATOM 809 CL3 CID A 1 40.751 8.456 33.699 1.00 20.31 INH1 END 

1-57. (canceled)
 58. A crystal consisting essentially of HDM2 amino acid residues 17-111 of (SEQ ID NO:1), with a ligand, wherein said ligand is a non-peptide small molecule inhibitor of HDM2, wherein said non-peptide small molecule inhibitor prevents HDM2 from interacting with p53.
 59. The crystal of claim 1 wherein said crystal has a spacegroup selected from the group consisting of a trigonal spacegroup of P3₂21 and a tetragonal spacegroup of P4₃2₁2.
 60. The crystal of claim 1, wherein the crystal effectively diffracts X-rays for determination of atomic coordinates to a resolution of at least about 3.0 Å.
 61. The crystal of claim 1 wherein said ligand is selected from the group consisting of (4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid; [8-Chloro-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid); and derivatives thereof.
 62. An isolated protein fragment comprising a binding pocket or active site defined by atomic structure coordinates of HDM2 amino acid residues 17-111 of SEQ ID NO:1 amino acid residues Ser¹⁷, Ile¹⁹, Leu⁸² and Arg⁹⁷ in Table 1 or Table
 2. 63. An isolated fragment of claim 62 linked to a solid support.
 64. A kit comprising a protein molecule fragment of claim
 62. 65. A method for the production of a crystal complex comprising an HDM2 polypeptide-ligand comprising: (a) contacting the HDM2 polypeptide with said ligand in a suitable solution comprising PEG and NaSCN; and, b) crystallizing said resulting complex of HDM2 polypeptide-ligand from said solution.
 66. The method of claim 65 wherein said PEG has an average molecular weight range from 100 to 1000, wherein said PEG is present in solution at a range from about 0.5% w/v to about 10% w/v and said NaSCN is present in solution at a range of from about 50 mM to about 150 mM.
 67. The method of claim 66 wherein said PEG has an average molecular weight of about 400 and is present in solution at about 2% w/v and said NaSCN is present in solution at about 100 mM.
 68. The method of claim 67 wherein said solution further comprises about 1.8-2.4 M (NH₄)₂SO₄ and about 100 mM buffer.
 69. A method for the production of a crystal of claim 1 comprising: complexing a peptide comprising a sequence selected from the group consisting of amino acids 17-111 of SEQ ID NO: 1 with a small molecule; concentrating said complex; and allowing said concentrated complex to crystallize.
 70. A method for the production of a crystal complex comprising: mixing 1-2 μl of HDM2 protein consisting of amino acids 17-111 of SEQ ID NO: 1 complexed with a small molecule and concentrated to ca. 10 mg/ml in a 1:1 ratio with well solution (1.8-2.4M (NH4)2SO4, 100 mM buffer pH. 6.5-9.0, 2% PEG 400, 100 mM NaSCN); placing said mixed solution on a glass cover slip; inverting the glass cover slip and sealing the glass cover slip over a reservoir of 500-1000 μl of well solution; incubating the glass cover slip at 4° C. for from about 3 to about 7 days to permit formation of crystals; and harvesting the crystals. 